That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance.

摘要: Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of ERK1/2. In many cases, tumour cells adapt to become addicted this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window tumour-selective growth inhibition. As result, inhibition by MEK1/2 inhibitors is an attractive strategy. Indeed, first inhibitor, vemurafenib, has now been approved clinical use, while evaluation at advanced stage. Despite progress, it apparent that quickly these new targeted agents so tumours with acquired resistance emerge within 6–9 months primary treatment. One major reasons typically respond undergoing G1 cell cycle arrest rather than dying. although invariably increases expression pro-apoptotic BCL2 family proteins, undergo minimal apoptosis. This cytostatic response may simply provide opportunity and acquire resistance. Here we discuss recent studies demonstrate combination pro-survival proteins synthetic lethal ERK1/2-addicted cells. effectively transforms into striking apoptotic death response. not only augments efficacy but delays onset agents, validating clinic. Linked Articles This article part themed section on Emerging Therapeutic Aspects Oncology. To view other articles visit http://dx.doi.org/10.1111/bph.2013.169.issue-8