Methods of identifying responses to map kinase inhibition therapy

Abstract

The invention provides methods and devices for determining molecular signatures in a cancer that predict response to a MARPK pathway inhibitor and methods of use of such signatures.

1 . A method comprising
 measuring in a cancer sample obtained from a subject having cancer   (1) expression of one or more resistance markers selected from the group consisting of BDNF, KCNMA1, PAPPA, CCDC80, RRAS, CLMP, EPHA2, HRH1, SCG5, TSPAN5, BEX1, TMEM200A, TGM2, CD163L1, S100A16, IGFBP6, ITGA3, LOC100130938, C12orf75, FBN2, CRIM1, COL6A2, and EFNB2 (“R1 markers”), and   (2) expression of
 (a) one or more resistance markers selected from the group consisting of DSE, CYR61, CDH13, PODXL, SERPINE1, NRP1, IL1B, BIRC3, AXL, NUAK1, TCF4, COL5A1, NTM, CCL2, IL1A and TPM1 (“R2 markers”), or 
 (b) one or more sensitive markers selected from the group consisting of IGSF11, FAM167B, MTUS1, GDF15, LINC00518, LRRK2, ID4, CMTM8, KIAA0226L, C11orf96, D4S234E, TBC1D16, TTYH2, LAMA1, PMEL, PROS1, KCNN2, ESRP1, TRIM63, RXRG, PLEKHH1, CPN1, PI15, GNPTAB, and RNF144A (“S1 markers”), or 
 (c) one or more sensitive markers selected from the group consisting of GYG2, TYR, SLC45A2, PLA1A, ST3GAL6, DCT, CITED1, RAB38, TNFRSF14, GALNT3, MREG, GPM6B, RRAGD, CAPN3, MLANA, and MITF (“S2 markers”). 
   
     
     
         2 . A method comprising
 measuring in a cancer sample obtained from a subject having cancer
 (1) expression of one or more sensitive markers selected from the group consisting of IGSF11, FAM167B, MTUS1, GDF15, LINC00518, LRRK2, ID4, CMTM8, KIAA0226L, C11orf96, D4S234E, TBC1D16, TTYH2, LAMA1, PMEL, PROS1, KCNN2, ESRP1, TRIM63, RXRG, PLEKHH1, CPN1, PI15, GNPTAB, and RNF144A (“S1 markers”), and 
 (2) expression of
 (a) one or more sensitive markers selected from the group consisting of GYG2, TYR, SLC45A2, PLA1A, ST3GAL6, DCT, CITED1, RAB38, TNFRSF14, GALNT3, MREG, GPM6B, RRAGD, CAPN3, MLANA, and MITF (“S2 markers”), or 
 (b) expression of one or more resistance markers selected from the group consisting of BDNF, KCNMA1, PAPPA, CCDC80, RRAS, CLMP, EPHA2, HRH1, SCG5, TSPAN5, BEX1, TMEM200A, TGM2, CD163L1, S100A16, IGFBP6, ITGA3, LOC100130938, C12orf75, FBN2, CRIM1, COL6A2, and EFNB2 (“R1 markers”), or 
 (c) one or more resistance markers selected from the group consisting of DSE, CYR61, CDH13, PODXL, SERPINE1, NRP1, IL1B, BIRC3, AXL, NUAK1, TCF4, COL5A1, NTM, CCL2, IL1A and TPM1 (“R2 markers”). 
 
   
     
     
         3 . A method comprising
 measuring in a cancer sample obtained from a subject having cancer
 (1) expression of two or more resistance markers selected from the group consisting of BDNF, KCNMA1, PAPPA, CCDC80, RRAS, CLMP, EPHA2, HRH1, SCG5, TSPAN5, BEX1, TMEM200A, TGM2, CD163L1, S100A16, IGFBP6, ITGA3, LOC100130938, C12orf75, FBN2, CRIM1, COL6A2, and EFNB2 (“R1 markers”), and/or 
 (2) expression of two or more sensitive markers selected from the group consisting of IGSF11, FAM167B, MTUS1, GDF15, LINC00518, LRRK2, ID4, CMTM8, KIAA0226L, C11orf96, D4S234E, TBC1D16, TTYH2, LAMA1, PMEL, PROS1, KCNN2, ESRP1, TRIM63, RXRG, PLEKHH1, CPN1, PI15, GNPTAB, and RNF144A (“S1 markers”). 
   
     
     
         4 . The method of  claim 1 , wherein the subject is human. 
     
     
         5 . The method of  claim 1 , wherein the cancer is a cancer treated with a MAPK pathway inhibitor. 
     
     
         6 . The method of  claim 1 , wherein the cancer is melanoma. 
     
     
         7 . The method of  claim 1 , wherein the cancer comprises a BRAF mutation. 
     
     
         8 . The method of  claim 1 , wherein the cancer is a melanoma having a BRAF mutation. 
     
     
         9 . The method of  claim 1 , wherein the subject has been or is being treated with a MAPK pathway inhibitor. 
     
     
         10 . The method of  claim 1 , wherein expression is mRNA expression. 
     
     
         11 . The method of  claim 1 , wherein expression is protein expression. 
     
     
         12 . The method of  claim 1 , further comprising altering a therapy to the subject if the subject presents a resistant phenotype. 
     
     
         13 - 35 . (canceled) 
     
     
         36 . The method of  claim 1 , further comprising identifying a cancer characterized as having
 (i) one or more of the R1 markers up-regulated and   (ii) one or more of the R2 markers up-regulated or   (iii) one or more of the S1 markers down-regulated or   (iv) one or more of the S2 markers down-regulated.   
     
     
         37 . The method of  claim 1 , further comprising identifying a cancer characterized as having
 (i) one or more of the R1 markers down-regulated and   (ii) one or more of the R2 markers down-regulated or   (iii) one or more of the S1 markers up-regulated or   (iv) one or more of the S2 markers up-regulated.   
     
     
         38 . The method of  claim 2 , further comprising identifying a cancer characterized as having
 (i) one or more of the S1 markers up-regulated and   (ii) one or more of the S2 markers up-regulated or   (iii) one or more of the R1 markers down-regulated or   (iv) one or more of the R2 markers down-regulated.   
     
     
         39 . The method of  claim 3 , further comprising identifying a cancer characterized as having
 (i) two or more of the R1 markers up-regulated, and optionally   (ii) two or more of the S1 markers down-regulated.   
     
     
         40 . The method of  claim 3 , further comprising identifying a cancer characterized as having
 (i) two or more of the S1 markers up-regulated, and optionally   (ii) two or more of the R1 markers down-regulated.