Combined MEK and BCL-2/XL Inhibition Is Effective in High-Grade Serous Ovarian Cancer Patient–Derived Xenograft Models and BIM Levels Are Predictive of Responsiveness

Abstract

Most patients with late-stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the proapoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/X L inhibitor (ABT-263) significantly reduced cell number, increased cell death, and displayed synergy in vitro in most models. In vivo, GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive modelsthose with high BIM at baseline that was increased with MEK inhibition and those with low basal BIM and high pERK levels. Models with low BIM and low pERK were nonresponsive. Our findings demonstrate that combined MEK and BCL-2/X L inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for the clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.

Development of a 3D functional assay and identification of biomarkers, predictive for response of high-grade serous ovarian cancer (HGSOC) patients to poly-ADP ribose polymerase inhibitors (PARPis): targeted therapy

“…Further, microarray experiments focused on comparing the gene expression patterns between 6 sensitive and 6 resistant AsPCs to both tested drugs, and consecutive IPA network and pathway analyses, were indicative for the predominant downregulation of numerous genes and networks with previously demonstrated roles in cancer chemoresistance in the PARPis-sensitive AsPCs, as compared to the PARPis-resistant AsPCs (see Additional file 7). Most of these genes/networks (comprising calpain, STAT1, ABCB1, LGALS8, CARD10, GST, LAMB1, PBX1, AHR, IFI16, the ATPase, the MAPK and MEK networks) were shown to be related to mechanisms of EOC chemoresistance, including association with advanced EOC stage and poor prognosis [73][74][75][76][77][78][79][80][81][82][83][84][85]. Interestingly, ABCB1 induction was also shown to define a common resistance mechanism in paclitaxel-and olaparib-resistant EOC cells [74,86].…”

MEK inhibitor resistance mechanisms and recent developments in combination trials

“…BCL-2/BCL-XL inhibition increases the efficacy of MEK inhibition in lung and pancreatic tumor cell lines [95]. Similarly, combined MEK and BCL-2/XL inhibition has also been shown to be effective in high-grade serous ovarian cancer patient--derived xenograft models [96]. Currently, a phase I/II clinical trial combining BCL-XL and MEKi has shown initial signs of efficacy, with a favorable disease control rate and durable partial response in patients with RAS-mutant gynecologic cancer [97].…”

Bcl‑2 family: Novel insight into individualized therapy for ovarian cancer (Review)

“…Of note, when combined with carboplatin and paclitaxel, ABT-263 exhibited additive activity in inducing apoptosis in vitro , which provided a rationale for the treatment of ovarian cancer with ABT-263 ( 91 ). Recently, a study found that the combination of MEK inhibitor and ABT-263 significantly inhibited tumor growth in vivo and in vitro in ovarian cancer ( 95 ).…”