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Mutant PIK3CA as a negative predictive biomarker for treatment with a highly selective PIM1 inhibitor in human colon cancer
Ist Teil von
Cancer biology & therapy, 2023-12, Vol.24 (1), p.2246208-2246208
Ort / Verlag
Taylor & Francis
Erscheinungsjahr
2023
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
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.