Co-targeting of BAX and BCL-XL proteins broadly overcomes resistance to apoptosis in cancer

Andrea Lopez,Swathi-Rao Narayanagari,Aristotelis Tsirigos,Felix Kopp,Lars Ulrik Nordstrøm,Miguel A Miranda-Roman,Evripidis Gavathiotis,Hua Zhou,Eduardo Vilar,Ping Chi,Denis E Reyna,Nadege Gitego

doi:10.1038/s41467-022-28741-7

Abstract

Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. Cancer cells commonly evade apoptosis through upregulation of the BCL-2 anti-apoptotic proteins; however, more resistant cancers also downregulate or inactivate pro-apoptotic proteins to suppress apoptosis. Here, we find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. The combination demonstrates synergistic efficacy in apoptosis-resistant cancer cells, xenografts, and patient-derived tumors while sparing healthy tissues. Additionally, functional assays and genomic markers are identified to predict sensitive tumors to the combination treatment. These findings advance the understanding of apoptosis resistance mechanisms and demonstrate a novel therapeutic strategy for cancer treatment.

Highlights

Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments
BTSA1.2 has the phenyl attached to the pyrazolone group as BTSA1, which provided significantly increased binding to BAX and apoptotic activity compared to BAM7 and Compound 4 that lack this phenyl group (Supplementary Table 1)
Since BCL-XL was suggested as a factor of resistance to direct BAX activation in our panel of cancer cell lines, we examined whether Navitoclax, a clinical BCL-XL/BCL-2 inhibitor, would be able to promote cytotoxicity against the same panel of cancer cell lines

Summary

Introduction

Deregulation of the BCL-2 family interaction network ensures cancer resistance to apoptosis and is a major challenge to current treatments. We find that apoptosis resistance in a diverse panel of solid and hematological malignancies is mediated by both overexpression of BCL-XL and an unprimed apoptotic state, limiting direct and indirect activation mechanisms of pro-apoptotic BAX. Both survival mechanisms can be overcome by the combination of an orally bioavailable BAX activator, BTSA1.2 with Navitoclax. BTSA1 induced BAX-mediated apoptosis in Acute Myeloid Leukemia (AML) in vitro and in vivo while sparing healthy tissues[38] While these studies provided the first proof-ofconcept for direct BAX activation as an effective treatment strategy in AML; the full therapeutic potential of this emerging strategy to other tumors resistant to apoptosis has not been exploited. Our findings provide insights into apoptotic resistance mechanisms and investigate the combination of direct BAX activation and BCL-XL inhibition as a novel therapeutic strategy that can broadly overcome apoptotic resistance in cancer

Methods

Results

Conclusion