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

Abstract

Oncogenic mutations in RAS or BRAF can drive the inappropriate activation of the ERK1/2. In many cases, tumour cells adapt to become addicted to this deregulated ERK1/2 signalling for their proliferation, providing a therapeutic window for tumour-selective growth inhibition. As a result, inhibition of ERK1/2 signalling by BRAF or MEK1/2 inhibitors is an attractive therapeutic strategy. Indeed, the first BRAF inhibitor, vemurafenib, has now been approved for clinical use, while clinical evaluation of MEK1/2 inhibitors is at an advanced stage. Despite this progress, it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6-9 months of primary treatment. One of the major reasons for this is that tumour cells typically respond to BRAF or MEK1/2 inhibitors by undergoing a G1 cell cycle arrest rather than dying. Indeed, although inhibition of ERK1/2 invariably increases the expression of pro-apoptotic BCL2 family proteins, tumour cells undergo minimal apoptosis. This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance. Here we discuss recent studies that demonstrate that combination of BRAF or MEK1/2 inhibitors with inhibitors of pro-survival BCL2 proteins is synthetic lethal for ERK1/2-addicted tumour cells. This combination effectively transforms the cytostatic response of BRAF and MEK1/2 inhibitors into a striking apoptotic cell death response. This not only augments the primary efficacy of BRAF and MEK1/2 inhibitors but delays the onset of acquired resistance to these agents, validating their combination in the clinic. LINKED ARTICLESThis article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi. org/10.1111/bph.2013.169.issue-8 Abbreviations A1, BCL2-related protein A1; AP1, activator protein 1; APAF1, apoptotic peptidase activating factor 1; ARAF, v-raf murine sarcoma 3611 viral oncogene homologue; BAD, BCL-XL/BCL2-associated death promoter; BAK, BCL2 homologous antagonist/killer; BAX, BCL2-associated x protein; BCL2, B-cell lymphoma 2; BCL-XL, B-cell lymphoma extra large; BH3, BCL2 homology domain 3; BID, BH3 interacting domain death agonist; BIK, BCL2-interacting killer; BIM, BCL2-interacting mediator of cell death; BMF, BCL2-modifying factor; BRAF, v-raf murine sarcoma viral oncogene homologue B1; CCND1, cyclin D1; CDC25A, cell division cycle 25 homologue A; CDK, cyclin-dependent kinase; CIP1, CDK-interacting protein 1; CRAF, v-raf-1 murine leukaemia viral oncogene homologue 1; CREB, cAMP responsive element binding protein; DKO, double knockout; EGFR, epidermal growth factor receptor; CRC, colorectal cancer; ELK1, ETS-like gene 1; EMT, epithelial-mesenchymal transition; ETS, v-ets erythroblastosis virus E26 oncogene homologue; FOXO3, forkhead box O 3; G1, growth phase 1; GSK3, glycogen synthase kinase 3; HIV, human immunodeficiency virus; HRAS, v-Ha-ras Harvey rat sarcoma viral oncogene homologue...

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

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Targeting BCL2-Proteins for the Treatment of Solid Tumours

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SHOC2 phosphatase-dependent RAF dimerization mediates resistance to MEK inhibition in RAS-mutant cancers

“…Relief of these negative feedbacks by pharmacological ERK-pathway inhibition results in signalling rebound and intrinsic resistance. In addition, the ERK-pathway is a key mediator of G1/S transition and MEKi’s have a predominantly cytostatic response that likely facilitates acquisition of drug resistance mechanisms 13 . Strikingly, in both RAS- and BRAF-mutant cells, most resistance mechanisms lead to ERK-pathway reactivation, highlighting the strong ‘oncogene addiction’ of these cancers to ERK-signalling.…”