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American Association for Cancer Research, Clinical Cancer Research, 6(29), p. 1102-1113, 2023

DOI: 10.1158/1078-0432.ccr-22-2550

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Synthetic Lethal Interaction with BCL-XL Blockade Deepens Response to Cetuximab in Patient-Derived Models of Metastatic Colorectal Cancer

This paper was not found in any repository, but could be made available legally by the author.
This paper was not found in any repository, but could be made available legally by the author.

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Abstract

AbstractPurpose:Approximately 20% of patients with RAS wild-type metastatic colorectal cancer (mCRC) experience objective responses to the anti-EGFR antibody cetuximab, but disease eradication is seldom achieved. The extent of tumor shrinkage correlates with long-term outcome. We aimed to find rational combinations that potentiate cetuximab efficacy by disrupting adaptive dependencies on antiapoptotic molecules (BCL2, BCL-XL, MCL1).Experimental Design:Experiments were conducted in patient-derived xenografts (PDX) and organoids (PDXO). Apoptotic priming was analyzed by BH3 profiling. Proapoptotic and antiapoptotic protein complexes were evaluated by co-immunoprecipitation and electroluminescence sandwich assays. The effect of combination therapies was assessed by caspase activation in PDXOs and by monitoring PDX growth.Results:A population trial in 314 PDX cohorts, established from as many patients, identified 46 models (14.6%) with appreciable (>50% tumor shrinkage) but incomplete response to cetuximab. From these models, 14 PDXOs were derived. Cetuximab primed cells for apoptosis, but only concomitant blockade of BCL-XL precipitated cell death. Mechanistically, exposure to cetuximab induced upregulation of the proapoptotic protein BIM and its sequestration by BCL-XL. Inhibition of BCL-XL resulted in displacement of BIM, which was not buffered by MCL1 and thereby became competent to induce apoptosis. In five PDX models, combination of cetuximab and a selective BCL-XL inhibitor triggered apoptosis and led to more pronounced tumor regressions and longer time to relapse after treatment discontinuation than cetuximab alone.Conclusions:In mCRC tumors that respond to cetuximab, antibody treatment confers a synthetic-lethal dependency on BCL-XL. Targeting this dependency unleashes apoptosis and increases the depth of response to cetuximab.