Combinations of mek inhibitors and raf kinase inhibitors and uses thereof

Abstract

This invention concerns combinations of inhibitors of MEK, Raf protein kinases, and other kinases including VEGFR1-3 and PDGFR-β. This invention also concerns pharmaceutical compositions comprising the compounds described herein and methods of use of the compounds and compositions described herein, including the use in the treatment and/or prevention of cancer and other hyperproliferative disorders.

1 . (canceled) 
     
     
         2 . A method comprising administering to a subject in need, a synergistic and therapeutically effective amount of at least one MEK protein kinase inhibitor and at least one Raf protein kinase inhibitor wherein (a) and (b) are in separate dosage forms or in the same dosage form, wherein:
 (a) the MEK protein kinase inhibitor is a compound selected from the group consisting of:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, polymorph, ester, or tautomer thereof and is present in an amount of 0.1 mg to 200 mg; and 
         (b) the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of 10 mg to 1.000 mg. 
       
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 2 , wherein the administration of the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor to a first patient provides an increase in apoptosis level at about day 7 compared to the combined apoptosis level by administration of either inhibitor alone. 
     
     
         5 . The method of  claim 3  wherein the administration of the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor to the first patient provides an increase in apoptosis level at about day 7 compared to the combined apoptosis level at about day 7 of (1) a second patient administered only the MEK protein kinase inhibitor and (2) a third patient administered only the Raf protein kinase inhibitor. 
     
     
         6 . The method of  claim 3  wherein the apoptosis levels are measured with an in vivo apoptosis assay. 
     
     
         7 . The pharmaceutical combinationmethod of  claim 3  wherein the increased apoptosis level of the first patient at about day 7 is greater than about a 50% increase in apoptosis. 
     
     
         8 . The method of  claim 3  wherein the increased apoptosis level of the first patient at about day 7 is about a 50% to about a 500% increase in apoptosis. 
     
     
         9 . The method of  claim 3  wherein the increased apoptosis level of the first patient at about day 7 is about a 100% to about a 500% increase in apoptosis. 
     
     
         10 . The method of  claim 3  wherein the increased apoptosis level of the first patient at about day 7 is about a 200% to about a 500% increase in apoptosis. 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 2 , wherein contacting a first sample of cancer cells with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor provides an increase in apoptosis level compared to the combined apoptosis level by administration of either inhibitor alone. 
     
     
         13 . The method of  claim 12  wherein contacting the first sample of cancer cells with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor provides an increase in apoptosis level at day 7 compared to the combined apoptosis level at day 7 of (1) a second sample provided by contacting cancer cells of the second sample with only the MEK protein kinase inhibitor and the (2) the apoptosis level of a third sample provided by contacting cancer cells of the third sample with only the Raf protein kinase inhibitor. 
     
     
         14 . The method of  claim 12  wherein the apoptosis levels are measured with an in vitro apoptosis assay. 
     
     
         15 . The method of  claim 12  wherein the increased apoptosis level of the first sample is greater than about 50% increase in apoptosis. 
     
     
         16 . The method of  claim 12  wherein the increased apoptosis level of the first sample is about a 50% to about a 500% increase in apoptosis. 
     
     
         17 . The method of  claim 12  wherein the increased apoptosis level of the first sample is about a 100% to about a 500% increase in apoptosis. 
     
     
         18 . The method of  claim 12  wherein the increased apoptosis level of the first sample is about a 200% to about a 500% increase in apoptosis. 
     
     
         19 . The method of  claim 12  wherein the number of cancer cells in the first sample contacted with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor, the number of cancer cells in the second sample contacted with only the MEK protein kinase inhibitor and the number of cancer cells in the third sample contacted with only the Raf protein kinase inhibitor are each a large enough sample to determine whether or not a difference between the groups is significant. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 2 , wherein an administration of the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor to a first patient provides a cell proliferation count at about day 7 compared to the difference in cell proliferation count by administration of either inhibitor alone. 
     
     
         22 . The method of  claim 21  wherein the administration of the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor to the first patient provides a cell proliferation count at about day 7 that is less than the difference between (1) the cell proliferation count at about day 7 of a second patient administered only the MEK protein kinase inhibitor and (2) the cell proliferation count at about day 7 of a third patient administered only the Raf protein kinase inhibitor. 
     
     
         23 . The method of  claim 21  wherein the cell proliferation levels are measured with an in vivo cell proliferation assay. 
     
     
         24 . The of  claim 21  wherein the cell proliferation count of the first patient administered the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor at about day 7 is about 20% to about 100% less than the difference between (1) the cell proliferation count at about day 7 of the second patient administered only the MEK protein kinase inhibitor and (2) the cell proliferation count at about day 7 of the third patient administered only the Raf protein kinase inhibitor. 
     
     
         25 . The method of  claim 21  wherein the cell proliferation count of the first patient administered the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor at about day 7 is at least about 20% less than the difference between (1) the cell proliferation count at about day 7 of the second patient administered only the MEK protein kinase inhibitor and (2) the cell proliferation count at about day 7 of the third patient administered only the Raf protein kinase inhibitor. 
     
     
         26 . The of  claim 21  wherein the cell proliferation count of the first patient administered the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor at about day 7 is about 20% to about 200% less than the difference between (1) the cell proliferation count at about day 7 of the second patient administered only the MEK protein kinase inhibitor and (2) the cell proliferation count at about day 7 of the third patient administered only the Raf protein kinase inhibitor. 
     
     
         27 . The of  claim 21  wherein the cell proliferation count of the first patient administered the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor at about day 7 is about 20% to about 100% less than the difference between (1) the cell proliferation count at about day 7 of the second patient administered only the MEK protein kinase inhibitor and (2) the cell proliferation count at about day 7 of the third patient administered only the Raf protein kinase inhibitor. 
     
     
         28 . The method of  claim 21  wherein the cell proliferation count of the first patient administered the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor at about day 7 is about 40% to about 100% less than the difference between (1) the cell proliferation count at about day 7 of the second patient administered only the MEK protein kinase inhibitor and (2) the cell proliferation count at about day 7 of the third patient administered only the Raf protein kinase inhibitor. 
     
     
         29 . The method of  claim 21  wherein the number of first patients administered the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor, the number of second patients administered only the MEK protein kinase inhibitor and the number of third patients administered only the Raf protein kinase inhibitor are each a large enough sample to determine whether or not a difference between the groups is significant. 
     
     
         30 . (canceled) 
     
     
         31 . The method of  claim 2 , wherein contacting a first sample of cancer cells with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor provides a cell proliferation count of the first sample that is less than the difference in cell proliferation count by administration of either inhibitor alone. 
     
     
         32 . The method of  claim 31  wherein contacting a first sample of cancer cells with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor provides a cell proliferation count of a first sample that is less than the difference between (1) the cell proliferation count of a second sample of cancer cells contacted with only the MEK protein kinase inhibitor and (2) the cell proliferation count of a third sample of cancer cells contacted with only the Raf protein kinase inhibitor. 
     
     
         33 . The method of  claim 31  wherein the cell proliferation count is measured with an in vitro cell proliferation assay. 
     
     
         34 . The method of  claim 31  wherein the cell proliferation count of the first sample contacted with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor is at least about 20% less than the difference between (1) the cell proliferation count of the second sample contacted only with a MEK protein kinase inhibitor and (2) the cell proliferation count of the third sample contacted only with a Raf protein kinase inhibitor. 
     
     
         35 . The method of  claim 31  wherein the cell proliferation count of the first sample contacted with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor is about 20% to about 200% less than the difference between (1) the cell proliferation count of the second sample contacted only with a MEK protein kinase inhibitor and (2) the cell proliferation count of the third sample contacted only with a Raf protein kinase inhibitor. 
     
     
         36 . The method of  claim 31  wherein the cell proliferation count of the first sample contacted with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor is about 20% to about 100% less than the difference between (1) the cell proliferation count of the second sample contacted only with a MEK protein kinase inhibitor and (2) the cell proliferation count of the third sample contacted only with a Raf protein kinase inhibitor. 
     
     
         37 . The method of  claim 31  wherein the cell proliferation count of the first sample contacted with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor is about 40% to about 100% less than the difference between (1) the cell proliferation count of the second sample contacted only with a MEK protein kinase inhibitor and (2) the cell proliferation count of the third sample contacted only with a Raf protein kinase inhibitor. 
     
     
         38 . The method of  claim 31  wherein the number of cancer cells in the first sample contacted with the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor, the number of cancer cells in the second sample contacted with only the MEK protein kinase inhibitor and the number of cancer cells in the third sample contacted with only the Raf protein kinase inhibitor are each a large enough sample to determine whether or not a difference between the groups is significant. 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 2  administration of the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor results in a decreased side effect compared to the combined side effect of administration by either inhibitor alone. 
     
     
         41 . The method of  claim 40  wherein an administration of the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor results in a lesser degree of a side effect at about day 7 of a first patient compared to the combined degree of the side effects at about day 7 of (1) a second patient administered only the MEK protein kinase inhibitor and (2) a third patient administered only the Raf protein kinase inhibitor. 
     
     
         42 . The method of  claim 40 , wherein the adverse side effect comprises a gastrointestinal or skin complication. 
     
     
         43 . The method of  claim 40 , wherein the adverse side effect is cardiac ischemia, hemorrhage, diarrhea, hypertension, hand and-foot skin irritation, gastrointestinal perforation, wound healing complications, teratogenicity and and embryofetal toxicity. 
     
     
         44 . A method for resensitizing cancer cells to treatment in a patient having or suspected of having a cancer resistant to an anticancer agent, comprising administering to the patient a therapeutically effective amount of at least one MEK protein kinase inhibitor and at least one Raf protein kinase inhibitor wherein (a) and (b) are in separate dosage forms or in the same dosage form, wherein:
 (a) the MEK protein kinase inhibitor is a compound selected from the group consisting of:   
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, polymorph, ester, or tautomer thereof and is present in an amount of 0.1 mg to 200 mg; and 
         (b) the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl-4-pyridyloxy)phenyl)urea and is present in an amount of 10 mg to 1,000 mg. 
       
     
     
         45 . The method of  claim 44 , wherein the cancer is resistant to treatment of a MEK protein kinase inhibitor. 
     
     
         46 . The method of  claim 45 , wherein the MEK protein kinase inhibitor is selected from the group consisting of CI-1040 (PD184352), GSK1120212, PD-0325901, PD-98059, PD-184161, PD-0318088, PD-184386, PD-171984, PD-170611, PD-177168, PD-184352, ARRY-438162, AZD6244/ARRY-886, AZD 8330, XL518, UO125, UO126, SL 327, and quercetin, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. 
     
     
         47 . The method of  claim 45 , wherein the MEK protein kinase inhibitor is selected from the group consisting of a compound of formula I and a compound of formula II. 
     
     
         48 . The method of  claim 44 , wherein the cancer is resistant to treatment of a Raf protein kinase inhibitor. 
     
     
         49 . The method of  claim 48 , wherein the Raf protein kinase inhibitor is selected from the group consisting of sorafenib (Bayer), XL71 (Exelixis), Raf 265 (Novartis), GW5074, and ZM336372, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. 
     
     
         50 . The method of  claim 48 , wherein the Raf protein kinase inhibitor is ISIS 5132 (Isis). 
     
     
         51 . The method of  claim 48 , wherein the Raf protein kinase inhibitor is sorafenib (Bayer). 
     
     
         52 . The method of  claim 44 , wherein the resistance is acquired resistance. 
     
     
         53 . The method of  claim 44 , wherein the resistance is de novo resistance. 
     
     
         54 . The method of  claim 44 , wherein the cancer is resistant to an anticancer agent. 
     
     
         55 . The method of  claim 54 , wherein the anticancer agent is selected from the group consisting of STI-571, imatinib, capecitibine (fluorouracil; OSI-774), adriamycin (ADM), gemcitabine, RTA 402, calcitriol, docetaxel, erlotinib, bevacizumab, cetuximab; oxaliplatin, dalteparin, temsirolimus, temozolomide, perifosine, or gefitinib. 
     
     
         56 . (canceled) 
     
     
         57 . The method of  claim 2 , wherein the molar ratio of the MEK protein kinase inhibitor to the Raf protein kinase inhibitor administered to a patient is about 100:1 to about 2.5:1. 
     
     
         58 . The method of  57  wherein the molar ratio is about 50:1 to about 5:1. 
     
     
         59 . The method of  57  wherein the molar ratio is about 45:1 to about 10:1. 
     
     
         60 . The method of  57  wherein the molar ratio is about 40:1 to about 20:1. 
     
     
         61 . The method of  57  wherein the molar ratio is about 30:1. 
     
     
         62 . The method of  claim 2 , wherein the therapeutically effective amount of the MEK protein kinase inhibitor is lower when administered in combination with the Raf protein kinase inhibitor than when administered alone. 
     
     
         63 . The method  claim 2 , wherein the therapeutically effective amount of the Raf protein kinase inhibitor is lower when administered in combination with the MET protein kinase inhibitor than when administered alone. 
     
     
         64 . (canceled) 
     
     
         65 . The method of  claim 2 , wherein administration of the combination of the MEK protein kinase inhibitor and the Raf protein kinase inhibitor to a first patient provides: (i) an increase in the area under the serum concentration time curve (AUC) of the MEK protein kinase inhibitor of the first patient compared to the AUC of the MEK protein kinase of a second patient when only the MEK protein kinase is administered to the second patient; or (ii) an increase in the AUC of the Raf protein kinase inhibitor of the first patient compared to the AUC of the Raf protein kinase of a second patient when only the Raf protein kinase is administered to the second patient. 
     
     
         66 . The method of  claim 2 , wherein the MEK protein kinase inhibitor is CI-1040 (PD184352), GSK1120212, PD-0325901, PD-98059, PD-184161, PD-0318088, PD-184386, PD-171984, PD-170611, PD-177168, PD-184352, ARRY-438162, AZD6244/ARRY-886, AZD 8330, XL518, UO125, UO126, SL 327, quercetin, or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. 
     
     
         67 . (canceled) 
     
     
         68 . (canceled) 
     
     
         69 . (canceled) 
     
     
         70 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 0.1 mg to about 200 mg. 
     
     
         71 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 0.5 mg to about 100 mg. 
     
     
         72 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 0.75 mg to about 75 mg. 
     
     
         73 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 1 mg to about 50 mg. 
     
     
         74 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 2 mg to about 25 mg. 
     
     
         75 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 3 mg to about 20 mg. 
     
     
         76 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 4 mg to about 15 mg. 
     
     
         77 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 5 mg to about 10 mg. 
     
     
         78 . The method of  claim 66  wherein the MEK protein kinase inhibitor is a compound of formula I, and is present in an amount of about 0.1 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4.0 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, and/or about 13 mg. 
     
     
         79 - 95  (canceled) 
     
     
         96 . The method of  claim 2 , wherein the Raf protein kinase inhibitor comprises an A-Raf inhibitor, a B-Raf inhibitor, or a C-Raf inhibitor (Raf-1 inhibitor). 
     
     
         97 . The method ef of  claim 2 , wherein the Raf protein kinase inhibitor comprises a B-Raf inhibitor. 
     
     
         98 . The method of  claim 2 , wherein the B-Raf inhibitor is Nexavar® (sorafenib, BAY43-9006, Bayer), XL71 (Exelixis), Raf 265 (Novartis), or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. 
     
     
         99 . The method of  claim 2 , wherein the B-Raf inhibitor is Nexavar® (Sorafenib, BAY43-9006, Bayer), or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. 
     
     
         100 . The combination or method of of  claim 2 , wherein the Raf protein kinase comprises a C-Raf protein kinase inhibitor. 
     
     
         101 . The method of  claim 2 , wherein the C-Raf protein kinase inhibitor is Nexavar® (sorafenib, BAY43-9006, Bayer), XL71 (Exelixis), Raf 265 (Novartis), ISIS 5132 (Isis), GW5074, ZM336372, or quercetin (red wine extract), or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. 
     
     
         102 . The method of  claim 2 , wherein the Raf protein kinase inhibitor is an antisense oligonucleotide. 
     
     
         103 . The method of  claim 2 , wherein the antisense oligonucleotide is ISIS 5132 (Isis). 
     
     
         104 . The method  claim 2 , wherein the Raf protein kinase inhibitor is Nexavar® (Sorafenib, BAY43-9006, Bayer), XL71 (Exelixis), SB386023, Raf 265 (Novartis), ISIS 5132 (Isis), Trapidil, GW5074, ZM336372, or quercetin (red wine extract), or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof. 
     
     
         105 . The method  claim 2  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea (Bayer). 
     
     
         106 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(triluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 10 mg to about 1,000 mg. 
     
     
         107 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 20 mg to about 900 mg. 
     
     
         108 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-me 1 hylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 20 mg to about 900 mg. 
     
     
         109 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 30 mg to about 850 mg. 
     
     
         110 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy and is present in an amount of about 40 mg to about 800 mg. 
     
     
         111 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 50 mg to about 750 mg. 
     
     
         112 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 75 mg to about 700 mg. 
     
     
         113 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 100 mg to about 650 mg. 
     
     
         114 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy and is present in an amount of about 150 mg to about 600 mg. 
     
     
         115 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 200 mg to about 500 mg. 
     
     
         116 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexavar®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 300 mg to about 400 mg. 
     
     
         117 . The method of  claim 105  wherein the Raf protein kinase inhibitor is Nexava®, the tosylate salt of N-(4-chloro-3-(trifluoromethyl)phenyl)-N′-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea and is present in an amount of about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or about 600 mg. 
     
     
         118 - 126 . (canceled) 
     
     
         127 . The method of  claim 2 , wherein the cancer is pancreatic, melanoma, colon, lung, liver, breast, prostate, or stomach cancer. 
     
     
         128 . The method of  claim 2 , wherein the cancer is pancreatic or stomach cancer. 
     
     
         129 . The method of  claim 2  wherein the cancer is pancreatic cancer. 
     
     
         130 . The method of  claim 2 , wherein the MEK protein kinase inhibitor and Raf protein kinase inhibitor comprise a fixed combination. 
     
     
         131 . The method  claim 2 , wherein the combination is a non-fixed combination. 
     
     
         132 . The method of  claim 131  wherein the MEK protein kinase inhibitor and Raf protein kinase inhibitor are administered simultaneously or concurrently in separate dosage forms. 
     
     
         133 . The method of  claim 131  wherein the MEK protein kinase inhibitor and Raf protein kinase inhibitor are administered sequentially in separate dosage forms. 
     
     
         134 . The method of  claim 133  wherein the MEK protein kinase inhibitor is administered before the Raf protein kinase inhibitor. 
     
     
         135 . The method of  claim 133  wherein the Raf protein kinase inhibitor is administered before the Raf protein kinase inhibitor. 
     
     
         136 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 1 second to about 72 hours of each other. 
     
     
         137 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 1 second of each other. 
     
     
         138 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 15 seconds of each other. 
     
     
         139 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 30 seconds of each other. 
     
     
         140 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 1 minute of each other. 
     
     
         141 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 1 hour of each other. 
     
     
         142 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 4 hours of each other. 
     
     
         143 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 8 hours of each other. 
     
     
         144 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 12 hours of each other. 
     
     
         145 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 24 hours of each other. 
     
     
         146 . The method of  claim 133  wherein the MEK protein kinase inhibitor and the Raf protein kinase inhibitor are administerer to a patient within about 48 hours of each other. 
     
     
         147 . The method of  claim 133  wherein the MEK protein kinase inhibitor is administered to the patient prior to the Raf protein kinase inhibitor. 
     
     
         148 . The combination or method of  claim 133  wherein the Raf protein kinase inhibitor is administered to the patient prior to the Raf protein kinase inhibitor. 
     
     
         149 . The method of any of the preceding claims of  claim 2 , wherein the combination is administered to a patient undergoing an additional therapy. 
     
     
         150 . The method of any of the preceding claims of  claim 2 , wherein the additional therapy is radiation therapy or chemotherapy, or both. 
     
     
         151 . The method of any of the preceding claims of  claim 2 , wherein the MEK protein kinase inhibitor binds to MEK with a binding affinity about 50 to about 500 times greater than its binding affinity for any other enzyme. 
     
     
         152 . The method of any of the preceding claims of  claim 2 , wherein the MEK protein kinase inhibitor binds to MEK with with a binding affinity of about 60 to about 250 times greater than its binding affinity for any other enzyme. 
     
     
         153 . The method of any of the preceding claims of  claim 2 , wherein the MEK protein kinase inhibitor binds to MEK with with a binding affinity of about 80 to about 125 times greater than its binding affinity for any other enzyme. 
     
     
         154 . The method of any of the preceding claims of  claim 2 , wherein the MEK protein kinase inhibitor binds to MEK with with a binding affinity of about 100 times greater than its binding affinity ofr any other enzyme. 
     
     
         155 . The method of any of the preceding claims of  claim 2 , wherein the MEK protein kinase inhibitor binds to MEK with with a binding affinity of about 100 times greater than its binding affinity for any other enzyme. 
     
     
         156 . The method of any of the preceding claims of  claim 2 , wherein the any other enzyme is a protein kinase. 
     
     
         157 . The pharmaceutical combination of  claim 2  wherein the cancer is liver or breast cancer. 
     
     
         158 . The pharmaceutical combination of  claim 2  wherein the cancer is liver cancer. 
     
     
         159 . The pharmaceutical combination of  claim 2  wherein the MEK protein kinase inhibitor and Raf protein kinase inhibitor are administered sequentially in separate dosage forms to a patient in need. 
     
     
         160 . The pharmaceutical combination of  claim 2  wherein the MEK protein kinase inhibitor is administered before the Raf protein kinase inhibitor to a patient in need. 
     
     
         161 . The pharmaceutical combination of  claim 2  wherein the Raf protein kinase inhibitor is administered before the MEK protein kinase inhibitor to a patient in need. 
     
     
         162 . The pharmaceutical combination of  claim 2  wherein the pharmaceutical combination is administered to a patient in need once or twice a day. 
     
     
         163 . The pharmaceutical combination of  claim 2  wherein the pharmaceutical combination is administered to a patient in need twice a day.