Acquired resistance to ERK1/2 pathway inhibitors in tumour cells; pathway adaptation and associated fitness deficits.

Simon J. Cook, The Babraham Institute, Cambridge, UK

The RAS-BRAF-MEK1/2-ERK1/2 signalling cascade is frequently hyperactivated in human cancers and is an attractive target for therapeutic intervention. BRAF inhibitors are highly effective against tumours with BRAF600E, but actually cause a paradoxical activation of ERK signaling in tumours with wild type BRAF. For this reason MEK and ERK inhibitors are also in development for treatment of tumours driven by RTK or RAS mutations. Regardless of early clinical successes the development of acquired resistance limits the efficacy of all of these agents. We have demonstrated that acquired resistance to specific, allosteric MEK1/2 inhibitors such as Selumetinib can arise through amplification of the driving oncogene, KRAS or BRAF, and pathway remodeling to re-instate normal ERK1/2 activity. We now find that this acquired resistance is reversible upon drug withdrawal; thus, the amplification of KRAS and BRAF that provides an advantage to the tumour cell in the presence of Selumetinib appears to confer a fitness deficit when the drug is withdrawn. We are investigating the mechanisms underlying the reversal of drug resistance. Finally, using alternative cell models, including isogenic lines lacking KRASMut, we are identifying novel mechanisms of acquired resistance to ERK1/2 pathway inhibitors. These studies exemplify the remarkable plasticity of the ERK1/2 signaling module that allow adaptation to highly specific pathway inhibitors.