Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity

Ryan S Soderquist,Peter S Winter,Kris C Wood,Kevin H Lin,Anika Agarwal,Esther Liu,Gray R Anderson,Lorin Crawford,Min Lu,Merve Cakir

doi:10.1038/s41467-018-05815-z

Ryan S Soderquist, Peter S Winter + Show 8 more

Open Access

https://doi.org/10.1038/s41467-018-05815-z

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Abstract

While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. Here we develop a drug screening approach to define the sensitivity of cancer cells from ten tissue types to all possible combinations of selective BCL-2, BCL-XL, and MCL-1 inhibitors and discover that most cell lines depend on at least one combination for survival. We demonstrate that expression levels of BCL-2 genes predict single mimetic sensitivity, whereas EMT status predicts synergistic dependence on BCL-XL+MCL-1. Lastly, we use a CRISPR/Cas9 screen to discover that BFL-1 and BCL-w promote resistance to all tested combinations of BCL-2, BCL-XL, and MCL-1 inhibitors. Together, these results provide a roadmap for rationally targeting BCL-2 family dependencies in diverse human cancers and motivate the development of selective BFL-1 and BCL-w inhibitors to overcome intrinsic resistance to BH3 mimetics.

Highlights

While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood
With these limitations in mind, we set out to address the following questions: What are the dependencies of diverse human cancers with respect to BCL-2, BCL-XL, MCL-1, and their combinations? What are the molecular features of tumors that drive these dependencies? which cancers fail to respond to BH3 mimetics, and how can this intrinsic resistance be overcome? To answer these questions, we developed a screening strategy to assess the sensitivity of cancer cell lines to all possible combinations of a selective BCL-2 inhibitor (ABT-199), a selective BCL-XL inhibitor (WEHI-539), and a selective MCL-1 inhibitor (A1210477)
A concentration of 10 μM was selected for this compound, as at this dose MCL-1 is fully inhibited without inhibitory effects on BCL-2 and BCL-XL8

Summary

Introduction

While inhibitors of BCL-2 family proteins (BH3 mimetics) have shown promise as anti-cancer agents, the various dependencies or co-dependencies of diverse cancers on BCL-2 genes remain poorly understood. To the best of our knowledge, no studies have systematically examined the dependencies of cancers on combinations of BCL-2 family proteins With these limitations in mind, we set out to address the following questions: What are the dependencies of diverse human cancers with respect to BCL-2, BCL-XL, MCL-1, and their combinations? We mapped cellular dependencies and co-dependencies on BCL-2, BCL-XL, and MCL-1 across a large number of primary and established cancer cell lines representing 10 distinct cancer types These data provide new insights into the landscape of sensitivity to BH3 mimetics in human cancers, revealing molecular determinants of sensitivity and a role for a novel endoplasmic reticulum (ER) stress-epithelialmesenchymal transition (EMT) axis in dictating the frequently observed synergy between BCL-XL and MCL-1 inhibitors in solid tumors. These findings may help guide the use of BH3 mimetics as precision therapies in defined cancers

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