Defining the susceptibility of colorectal cancers to BH3-mimetic compounds
Ming-Jie Luo1,2, Michelle Palmieri1,3, Chris D Riffkin1
1The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Abstract:
Novel targets are required to improve the outcomes for patients with colorectal cancers. In this regard, the selective inhibitor of the pro-survival protein BCL2, venetoclax, has proven highly effective in several hematological malignancies. In addition to BCL2, potent and highly selective small molecule inhibitors of its relatives, BCLxL and MCL1, are now available, prompting us to investigate the susceptibility of colorectal cancers to the inhibition of one or more of these pro-survival proteins. While targeting BCLxL, but not BCL2 or MCL1, on its own had some impact, most (15/17) of the immortalized colorectal cancer cell lines studied were efficiently killed by the combined targeting of BCLxL and MCL1. Importantly, these in vitro findings were confirmed in a xenograft model and, interestingly, in all (5/5) patient derived tumor organoids evaluated. Our results lend strong support to the notion that BCLxL and MCL1 are highly promising targets for further evaluation in efforts to improve the treatment of colorectal cancers.
Insights
Targeting BCLxL and MCL1 shows promise for colorectal cancer treatment. Combined inhibition effectively killed cancer cells in lab studies and patient-derived organoids, suggesting new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Colorectal cancer (CRC) necessitates novel therapeutic targets for improved patient outcomes.
- Selective inhibitors of BCL2 family proteins, including BCLxL and MCL1, are emerging as potential cancer treatments.
Purpose of the Study:
- To investigate the efficacy of inhibiting pro-survival proteins BCLxL and MCL1, individually and in combination, in colorectal cancer models.
- To evaluate the potential of BCLxL and MCL1 as therapeutic targets for CRC.
Main Methods:
- Screening of colorectal cancer cell lines using selective small molecule inhibitors of BCL2, BCLxL, and MCL1.
- In vitro validation in immortalized cell lines and patient-derived tumor organoids.
- In vivo assessment using a xenograft mouse model.
Main Results:
- Targeting BCLxL alone showed limited impact.
- Combined inhibition of BCLxL and MCL1 demonstrated significant efficacy, leading to efficient killing of most (15/17) colorectal cancer cell lines.
- In vitro findings were corroborated in a xenograft model and all tested patient-derived tumor organoids (5/5).
Conclusions:
- BCLxL and MCL1 are highly promising therapeutic targets for colorectal cancer.
- Combined targeting of BCLxL and MCL1 warrants further investigation for improving CRC treatment strategies.
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