Abstract IA10: Finding vulnerabilities of drug resistant cancers

Intrinsic and acquired drug resistance represent major obstacles to effective cures for cancer. Understanding these mechanisms is instrumental for the design of strategies to counter these resistance mechanisms.In my presentation, I will focus on an example of intrinsic drug resistance and one of acquired drug resistance. As an example of intrinsic drug resistance, I will discuss the lack of response to MEK inhibitors seen in KRAS mutant tumors of various. The consistently poor response of KRAS mutant tumors to inhibition of its downstream kinases is unexpected, as it defies the concept of oncogene addiction. Nevertheless, a subset of tumors responds well to MEK inhibition, but it remains unclear which biomarkers can be used to identify MEK inhibitor sensitive cancer cells. I will demonstrate that inactivating mutations in both MAP3K1 and MAP2K4 will confer strong sensitivity to MEK inhibition in cancers of any tissue origin. Given that most major cancers have a mutation rate in these two genes of around 10%, the use of these mutations may help select patient subgroups that benefit from MEK inhibitor therapy.As an example of acquired drug resistance, I will discuss resistance of BRAF(V600E) mutant melanomas to drugs that target the BRAF and/or MEK kinases. This acquired resistance is almost always caused by reactivation of signaling through this pathway in the presence of drug. Drug withdrawal in such patients leads to a further hyper-activation of MAPK pathway, leading to a ...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Finding Synthetic Lethal Interactions through Functional Genomics: Oral Presentations - Invited Abstracts Source Type: research