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Cell Death Dis. 2018 Jul 3;9(7):739. doi: 10.1038/s41419-018-0776-6.

PIK3CA mutations confer resistance to first-line chemotherapy in colorectal cancer.

Author information

1
Department of Oncology, General Hospital of Jinan Military Command PLA, Jinan, 250031, China.
2
Department of Pathology, 401 People's Liberation Army Hospital, Qingdao, 266071, China.
3
Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
4
Department of Oncology, Liaocheng Cancer Hospital, Liaocheng, 252000, China.
5
Department of Oncology, General Hospital of Jinan Military Command PLA, Jinan, 250031, China. jingwangbi@outlook.com.

Abstract

Chemotherapy represents an important treatment option for colorectal cancer (CRC), but only half of the patients benefit from these regimens. We explored the potential predicting value and mechanism of PIK3CA mutation in CRC chemotherapy. CRC specimens from 440 patients were retrospectively collected and examined with a fluorescence PCR-based method. The correlation of first-line chemotherapy response and PIK3CA mutation was evaluated according to follow-up and medical records. The underlying mechanism of PIK3CA mutation in chemotherapy resistance was assessed with CRC tumors and primary cells. The mutation frequency of the PIK3CA gene in CRC patients was 9.55%, which was correlated with late TNM staging and lower histological grade. The CRC patients with PIK3A mutation showed worse response to first-line chemotherapy than those without PIK3CA mutation. PIK3A mutation tumor cells showed poor sensitivity to first-line chemotherapy in vitro and in vivo. PIK3CA mutation induced PI3K/Akt signaling activation to increase LGR5+ CRC stem cells survival and proliferation, from which lead to chemotherapy resistance. Furthermore, PIK3CA mutation/LGR5+ expression was an independent detrimental factor for CRC patients. Our findings indicated that PIK3CA mutation induced PI3K/Akt activation contributed to CRC stem cells survival and proliferation, from which cells further resistance to chemotherapy. PIK3CA mutation/LGR5+ expression was a potential biomarker for monitoring chemotherapy resistance in CRC.

PMID:
29970892
PMCID:
PMC6030128
DOI:
10.1038/s41419-018-0776-6
[Indexed for MEDLINE]
Free PMC Article

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