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Ref Type Journal Article
PMID (28424201)
Authors Xu JM, Wang Y, Wang YL, Wang Y, Liu T, Ni M, Li MS, Lin L, Ge FJ, Gong C, Gu JY, Jia R, Wang HF, Chen YL, Liu RR, Zhao CH, Tan ZL, Jin Y, Zhu YP, Ogino S, Qian ZR
Title PIK3CA Mutations Contribute to Acquired Cetuximab Resistance in Patients with Metastatic Colorectal Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 16
Date 2017 Aug 15
URL
Abstract Text Purpose: Mutations in KRAS are considered to be the main drivers of acquired resistance to epidermal growth factor receptor (EGFR) blockade in patients with metastatic colorectal cancer (mCRC). However, the potential role of other genes downstream of the EGFR signaling pathway in conferring acquired resistance has not been extensively investigated.Experimental Design: Using circulating tumor DNA (ctDNA) from patients with mCRC and with acquired cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method to screen for low-abundance somatic mutations in a panel of genes that encode components of the EGFR signaling pathway. Mutations with significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences of the identified mutations were validated in cultured cells.Results: We analyzed 32 patients with acquired cetuximab resistance in a development cohort. Of them, seven (22%) carried five novel PIK3CA mutations, whereas eight (25%) carried previously reported KRAS mutations. Functional studies showed that novel PIK3CA mutations (all in exon 19; p.K944N, p.F930S, p.V955G, p.V955I, and p.K966E) promote cell viability in the presence of cetuximab. Only one novel PIK3CA mutation (p.K944N) was verified in one of the 27 patients with acquired resistance in a validation cohort, simultaneous KRAS and PIK3CA hotspot mutations were detected in two patients. Among the above 59 acquired resistance patients, those with PIK3CA or RAS mutations detected in ctDNA showed a pronounced decrease in progression-free survival than patients with no mutation.Conclusions: The PIK3CA mutations may potentially contribute to acquired cetuximab resistance in patients with mCRC. Clin Cancer Res; 23(16); 4602-16. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
PIK3CA F930S missense gain of function - predicted PIK3CA F930S lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). F930S results in activation of Pik3ca signaling as indicated by increased phosphorylation of Akt and Mapk3/Mapk1 (Erk1/2), and confers resistance to Erbitux (cetuximab) in culture (PMID: 28424201) and therefore, is predicted to result in a gain of Pik3ca protein function. Y
PIK3CA K944N missense gain of function - predicted PIK3CA K944N lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). K944N results in activation of Pik3ca signaling as indicated by increased phosphorylation of Akt and Mapk3/Mapk1 (Erk1/2), and confers resistance to Erbitux (cetuximab) in culture (PMID: 28424201) and therefore, is predicted to result in a gain of Pik3ca protein function. Y
PIK3CA K966E missense gain of function - predicted PIK3CA K966E lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). K966E results in activation of Pik3ca signaling as indicated by increased phosphorylation of Akt and Mapk3/Mapk1 (Erk1/2), and confers resistance to Erbitux (cetuximab) in culture (PMID: 28424201) and therefore, is predicted to result in a gain of Pik3ca protein function. Y
PIK3CA L938* nonsense gain of function - predicted PIK3CA L938* results in a premature truncation of the Pik3ca protein at amino acid 938 of 1068 (UniProt.org). L938* results in activation of Pik3ca signaling as indicated by increased phosphorylation of Akt and Mapk3/Mapk1 (Erk1/2) in culture (PMID: 28424201) and therefore, is predicted to result in a gain of Pik3ca protein function.
PIK3CA V952A missense gain of function - predicted PIK3CA V952A lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). V952A results in activation of Pik3ca signaling as indicated by increased phosphorylation of Akt and Mapk3/Mapk1 (Erk1/2), and confers resistance to Erbitux (cetuximab) in culture (PMID: 28424201) and therefore, is predicted to result in a gain of Pik3ca protein function. Y
PIK3CA V955G missense gain of function - predicted PIK3CA V955G lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). V955G results in activation of Pik3ca signaling as indicated by increased phosphorylation of Akt and Mapk3/Mapk1 (Erk1/2), and confers resistance to Erbitux (cetuximab) in culture (PMID: 28424201) and therefore, is predicted to result in a gain of Pik3ca protein function. Y
PIK3CA V955I missense gain of function - predicted PIK3CA V955I lies within the PI3K/PI4K domain of the Pik3ca protein (UniProt.org). V955I results in activation of Pik3ca signaling as indicated by increased phosphorylation of Akt and Mapk3/Mapk1 (Erk1/2), and confers resistance to Erbitux (cetuximab) in culture (PMID: 28424201) and therefore, is predicted to result in a gain of Pik3ca protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA E545K colorectal cancer resistant Cetuximab + Fluorouracil Preclinical - Cell culture Actionable In a preclinical study, colorectal cancer cells over expressing PIK3CA E545K were resistant to Erbitux (cetuximab) and Fluorouracil combination treatment in culture (PMID: 28424201). 28424201
PIK3CA H1047R colorectal cancer resistant Cetuximab + Fluorouracil Preclinical - Cell culture Actionable In a preclinical study, colorectal cancer cells over expressing PIK3CA H1047R were resistant to Erbitux (cetuximab) and Fluorouracil combination treatment in culture (PMID: 28424201). 28424201
PIK3CA V955G colorectal cancer resistant Cetuximab + Fluorouracil Case Reports/Case Series Actionable In a clinical study, PIK3CA V955G was identified as a potential mechanism for acquired Erbitux (cetuximab) resistance in a colorectal cancer patient, which is supported by cell culture studies demonstrating resistance to Erbitux (cetuximab) and Fluorouracil combination treatment in colorectal cancer cells over expressing PIK3CA V955G (PMID: 28424201). 28424201
PIK3CA K944N colorectal cancer resistant Cetuximab + Fluorouracil Case Reports/Case Series Actionable In a clinical study, PIK3CA K944N was identified as a potential mechanism for acquired Erbitux (cetuximab) resistance in two colorectal cancer patients, which is supported by cell culture studies demonstrating resistance to Erbitux (cetuximab) and Fluorouracil combination treatment in colorectal cancer cells over expressing PIK3CA K944N (PMID: 28424201). 28424201
PIK3CA V952A colorectal cancer resistant Cetuximab + Fluorouracil Case Reports/Case Series Actionable In a clinical study, PIK3CA V952A was identified as a potential mechanism for acquired Erbitux (cetuximab) resistance in a colorectal cancer patient, which is consistent with cell culture studies demonstrating moderate resistance to Erbitux (cetuximab) and Fluorouracil combination treatment in colorectal cancer cells over expressing PIK3CA V952A (PMID: 28424201). 28424201
PIK3CA E542K colorectal cancer resistant Cetuximab + Fluorouracil Preclinical - Cell culture Actionable In a preclinical study, colorectal cancer cells over expressing PIK3CA E542K were resistant to Erbitux (cetuximab) and Fluorouracil combination treatment in culture (PMID: 28424201). 28424201
PIK3CA F930S colorectal cancer resistant Cetuximab + Fluorouracil Case Reports/Case Series Actionable In a clinical study, PIK3CA F930S was identified as a potential mechanism for acquired Erbitux (cetuximab) resistance in a colorectal cancer patient, which is consistent with cell culture studies demonstrating moderate resistance to Erbitux (cetuximab) and Fluorouracil combination treatment in colorectal cancer cells over expressing PIK3CA F930S (PMID: 28424201). 28424201
PIK3CA K966E colorectal cancer resistant Cetuximab + Fluorouracil Clinical Study - Cohort Actionable In a clinical study, PIK3CA K966E was identified as a potential mechanism for acquired Erbitux (cetuximab) resistance in a colorectal cancer patient, which is supported by cell culture studies demonstrating resistance to Erbitux (cetuximab) and Fluorouracil combination treatment in colorectal cancer cells overexpressing PIK3CA K966E (PMID: 28424201). 28424201
PIK3CA V955I colorectal cancer resistant Cetuximab + Fluorouracil Case Reports/Case Series Actionable In a clinical study, PIK3CA V955I was identified as a potential mechanism for acquired Erbitux (cetuximab) resistance in a colorectal cancer patient, which is supported by cell culture studies demonstrating resistance to Erbitux (cetuximab) and Fluorouracil combination treatment in colorectal cancer cells over expressing PIK3CA V955I (PMID: 28424201). 28424201