Methods and pharmaceutical compositions for the treatment of cancers associated with activation of the mapk pathway

Abstract

The response of subjects suffering from cancer to MAPK inhibitors is dramatically impaired by secondary resistances and rapid relapse. So far, the molecular mechanisms driving these resistances are not completely understood. The inventors show that expression of 10 SLITRK6 (SLIT and NTRK-like family, member 6) is induced by a MAPK inhibitor (e.g. Vemurafenib) and the inhibition of its induction in presence of the MAPK inhibitor induces synthetic lethality. Thus, the only inhibition of SLITRK6 by an inhibitor ot activity or expression should potentiate the antitumor effect of the MAPK inhibitors and avoid the emergence of a resistance to those compounds. Furthermore the specific expression of 15 SLITRK6 also paves the way of strategies based on depletion of the residual cancer cells by targeting them with anti-SLITRK6 antibodies capable of mediating ADCC or antibody-drug conjugates binding to SLITRK6.

1 - 15 . (canceled) 
     
     
         16 . A method of treating a cancer characterized by at least one mutation in the MAPK pathway in a subject in need thereof, comprising:
 administering to the subject a therapeutically effective combination comprising
 at least one MAPK inhibitor, and 
 an agent that inhibits activity of SLITRK6 and mediates cell death of SLITRK6 expressing cancer cells. 
   
     
     
         17 . The method of  claim 16  wherein the agent is an siRNA to SLITRK6. 
     
     
         18 . The method of  claim 16  wherein the at least one mutation is in NRAS or BRAF. 
     
     
         19 . The method of  claim 16  wherein the subject suffers from a cancer selected from the group consisting of melanoma, multiple myeloma, lung cancer, colorectal cancer, thyroid carcinoma, blood cancer, leukemia, and lymphoma. 
     
     
         20 . The method of  claim 16  wherein the MAPK inhibitor is selected from the group consisting of MEK inhibitors and BRAF inhibitors. 
     
     
         21 . The method of  claim 16  wherein the therapeutically effective combination comprises a BRAF inhibitor, a MEK inhibitor and the agent that inhibits activity of SLITRK6 and mediates cell death of SLITRK6 expressing cancer cells. 
     
     
         22 . The method of  claim 21  wherein the agent is an siRNA to SLITRK6. 
     
     
         23 . The method of  claim 16  wherein the at least one MAPK inhibitor is vemurafenib. 
     
     
         24 . A method of determining and treating relapse in a subject suffering from a cancer after a treatment regimen comprising administration of a MAPK inhibitor, comprising
 i) detecting the expression of SLITRK6 in a tumor sample obtained from the subject;   ii) concluding that the subject has relapsed when the expression of SLITRK6 is detected at step i); and   iii) administering to the subject a therapeutically effective combination comprising at least one MAPK inhibitor and an agent that inhibits activity of SLITRK6 and mediates cell death of SLITRK6 expressing cancer cells.   
     
     
         25 . The method of  claim 24  wherein the agent is an siRNA to SLITRK6. 
     
     
         26 . The method of  claim 24  wherein the tumor sample is from a tumor resected from the subject or is from a biopsy performed in the primary tumor of the subject or a metastasis distant from the primary tumor of the subject, or is a sample of circulating tumor cells. 
     
     
         27 . The method of  claim 24  wherein the step of detecting is performed by detecting the quantity of mRNA encoding for SLITRK6 or by immunodetection of SLITRK6 protein.