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Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon
Yoon Sun Park1,2, Joseph Kim1,2, Yea Seong Ryu1
1Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea.
Abstract:
Significant improvement in targeted therapy for colorectal cancer (CRC) has occurred over the past few decades since the approval of the EGFR inhibitor cetuximab. However, cetuximab is used only for patients possessing the wild-type oncogene KRAS, NRAS, and BRAF, and even most of these eventually acquire therapeutic resistance, via activation of parallel oncogenic pathways such as RAS-MAPK or PI3K/Akt/mTOR. The two aforementioned pathways also contribute to the development of therapeutic resistance in CRC patients, due to compensatory and feedback mechanisms. Therefore, combination drug therapies (versus monotherapy) targeting these multiple pathways may be necessary for further efficacy against CRC. In this study, we identified PIK3CA mutant (PIK3CA MT) as a determinant of resistance to SMI-4a, a highly selective PIM1 kinase inhibitor, in CRC cell lines. In CRC cell lines, SMI-4a showed its effect only in PIK3CA wild type (PIK3CA WT) cell lines, while PIK3CA MT cells did not respond to SMI-4a in cell death assays. In vivo xenograft and PDX experiments confirmed that PIK3CA MT is responsible for the resistance to SMI-4a. Inhibition of PIK3CA MT by PI3K inhibitors restored SMI-4a sensitivity in PIK3CA MT CRC cell lines. Taken together, these results demonstrate that sensitivity to SMI-4a is determined by the PIK3CA genotype and that co-targeting of PI3K and PIM1 in PIK3CA MT CRC patients could be a promising and novel therapeutic approach for refractory CRC patients.
Insights
PIK3CA mutations confer resistance to PIM1 inhibitor SMI-4a in colorectal cancer (CRC). Combining PI3K and PIM1 inhibitors may overcome this resistance in PIK3CA-mutant CRC patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Targeted therapies like cetuximab for colorectal cancer (CRC) face resistance, often due to activation of parallel oncogenic pathways (RAS-MAPK, PI3K/Akt/mTOR).
- Combination therapies are increasingly necessary to overcome resistance mechanisms in CRC treatment.
- Identifying genetic determinants of drug response is crucial for personalized CRC therapy.
Purpose of the Study:
- To investigate the role of PIK3CA mutations in mediating resistance to the PIM1 kinase inhibitor SMI-4a in colorectal cancer.
- To explore the potential of combination therapy targeting PI3K and PIM1 in PIK3CA-mutant CRC.
Main Methods:
- Utilized colorectal cancer (CRC) cell lines with varying PIK3CA genotypes (wild-type and mutant).
- Assessed sensitivity to SMI-4a in cell death assays.
- Conducted in vivo xenograft and patient-derived xenograft (PDX) experiments.
- Investigated the effect of PI3K inhibitors on restoring SMI-4a sensitivity in PIK3CA-mutant CRC cells.
Main Results:
- SMI-4a demonstrated efficacy only in PIK3CA wild-type (PIK3CA WT) CRC cell lines.
- PIK3CA mutant (PIK3CA MT) CRC cell lines exhibited resistance to SMI-4a.
- In vivo studies confirmed PIK3CA MT as a determinant of SMI-4a resistance.
- Co-inhibition of PI3K restored SMI-4a sensitivity in PIK3CA MT CRC cells.
Conclusions:
- Sensitivity to the PIM1 inhibitor SMI-4a is dictated by the PIK3CA genotype in colorectal cancer.
- Targeting both PI3K and PIM1 represents a novel therapeutic strategy for PIK3CA-mutant, refractory CRC patients.
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