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

Abstract

Purpose: 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 anti-apoptotic molecules (BCL2, BCL-XL, MCL1). Experimental Design: Experiments were conducted in patient-derived xenografts (PDXs) and organoids (PDXOs). Apoptotic priming was analyzed by BH3 profiling. Pro- and anti-apoptotic 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 pro-apoptotic 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 5 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.

Tolerance to colibactin correlates with homologous recombination proficiency and resistance to irinotecan in colorectal cancer cells

“…PDOs #6 and #7 were established as previously described. 52 Organoids were tested for Mycoplasma and maintained at 37°C in a humidified atmosphere of 5% CO2. All the PDOs were cultured in Cultrex Basement Membrane Extract (BME) Type 2 (Amsbio) with ENAS medium.…”

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency

“…Although inhibitors of Bcl-2 and Bcl-xL are effective in treating hematopoietic malignancies [ 17 ], efficacy is limited in primary solid cancers including GC partly because of a complex microenvironment that promotes cancer cell survival and resistance to treatment. Clinical trials of inhibitors of the Bcl-2 family in advanced GC have shown mixed results, and application in GC is currently limited [ 18 , 19 ]. However, a potential window for targeting Bcl-2 family members may arise during metastasis of solid tumors [ 9 ], where circulating tumor cells or colonizing micrometastatic foci maintain a high level of cancer stemness and are less strongly influenced by the microenvironment, with similarities to hematopoietic malignancies.…”

“…However, a potential window for targeting Bcl-2 family members may arise during metastasis of solid tumors [ 9 ], where circulating tumor cells or colonizing micrometastatic foci maintain a high level of cancer stemness and are less strongly influenced by the microenvironment, with similarities to hematopoietic malignancies. In addition, combining Bcl-2 family inhibition with other strategies can suppress metastasis in solid cancers [ 18 ]. Combination strategies guided by biomarkers to predict the response of inhibitors of the Bcl-2 family in the treatment of metastatic advanced GC have been suggested as a potential solution to the limited effectiveness of these inhibitors in GC.…”