Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer
Anna-Lena Scherr1, Andreas Mock1,2,3, Georg Gdynia4
1Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120, Heidelberg, Germany.
Abstract:
Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.
Insights
Targeting BCL-XL shows promise for treating colorectal cancer (CRC). Inhibiting this protein effectively kills CRC cells and enhances chemotherapy, offering a new therapeutic strategy for this deadly disease.
Area of Science:
- Oncology
- Molecular Biology
Background:
- Metastatic colorectal cancer (CRC) is a major cause of cancer mortality.
- Therapy resistance in CRC necessitates novel treatment strategies.
Purpose of the Study:
- Evaluate high-affinity inhibitors of antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1) for CRC treatment.
- Identify overactivated antiapoptotic BCL-2 proteins in CRC.
Main Methods:
- RNA sequencing analysis of >1500 patients for protein activity prediction.
- Pharmacologic and genetic inhibition of BCL-XL in CRC cell lines.
- Assessed combined treatment of BCL-XL inhibition with chemotherapy in vitro, murine models, and ex vivo CRC tissues.
Main Results:
- BCL-XL identified as the sole overactivated antiapoptotic BCL-2 protein in CRC.
- BCL-XL inhibition induced apoptosis in human CRC cell lines.
- Targeting BCL-XL potentiated chemotherapy efficacy across multiple preclinical models.
Conclusions:
- Targeting BCL-XL is a safe and effective strategy in preclinical CRC models.
- These findings support the clinical translation of BCL-XL inhibitors for CRC therapy.
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