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BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors
Le Zhang1,2, Prashanthi Ramesh1,2, Maxime Steinmetz1
1Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Abstract:
Colorectal cancer (CRC) is a heterogeneous disease, which in part explains the differential response to chemotherapy observed in the clinic. BH3 mimetics, which target anti-apoptotic BCL-2 family members, have shown potential in the treatment of hematological malignancies and offer promise for the treatment of solid tumors as well. To gain a comprehensive understanding of the response to BH3 mimetics in CRC and the underlying molecular factors predicting sensitivity, we screened a panel of CRC cell lines with four BH3 mimetics targeting distinct anti-apoptotic BCL-2 proteins. Treatment with compounds alone and in combination revealed potent efficacy of combined MCL-1 and BCL-XL inhibition in inducing CRC cell death, irrespective of molecular features. Importantly, expression of the anti-apoptotic protein target of BH3 mimetics on its own did not predict sensitivity. However, the analysis did identify consensus molecular subtype (CMS) specific response patterns, such as higher resistance to single and combined BCL-2 and MCL-1 inhibition in CMS2 cell lines. Furthermore, analysis of mutation status revealed that KRAS mutant cell lines were more resistant to MCL-1 inhibition. Conclusively, we find that CRC cell lines presented with distinct responses to BH3 mimetics that can in part be predicted by their CMS profile and KRAS/BRAF mutations. Overall, almost all CRC lines share sensitivity in the nanomolar range to combined MCL-1 and BCL-XL targeting suggesting that this would be the preferred approach to target these cancers.
Insights
BH3 mimetics targeting MCL-1 and BCL-XL show potent efficacy in colorectal cancer (CRC) cell death. Combined inhibition is effective across CRC subtypes, with resistance linked to specific molecular features like CMS2 and KRAS mutations.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Colorectal cancer (CRC) exhibits heterogeneity, leading to varied responses to chemotherapy.
- BH3 mimetics, targeting anti-apoptotic BCL-2 proteins, show promise for solid tumors beyond hematological malignancies.
Purpose of the Study:
- To comprehensively understand BH3 mimetic response in CRC.
- To identify molecular factors predicting sensitivity to BH3 mimetics in colorectal cancer.
Main Methods:
- Screening of CRC cell lines using four BH3 mimetics targeting distinct anti-apoptotic BCL-2 proteins.
- Assessment of cell death induction with single and combined BH3 mimetic treatments.
- Analysis of molecular features including consensus molecular subtype (CMS) and mutation status (KRAS, BRAF).
Main Results:
- Combined MCL-1 and BCL-XL inhibition demonstrated potent CRC cell death induction, independent of most molecular features.
- Sensitivity was not predicted by the expression of individual anti-apoptotic protein targets.
- Consensus molecular subtype (CMS) and KRAS/BRAF mutation status influenced response, with CMS2 and KRAS mutant cell lines showing increased resistance to certain inhibitors.
- Nearly all CRC cell lines exhibited nanomolar sensitivity to combined MCL-1 and BCL-XL targeting.
Conclusions:
- BH3 mimetics targeting MCL-1 and BCL-XL are highly effective in inducing colorectal cancer cell death.
- Colorectal cancer cell response to BH3 mimetics can be predicted by CMS profile and KRAS/BRAF mutations.
- Combined MCL-1 and BCL-XL inhibition represents a promising therapeutic strategy for colorectal cancer.
