Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	16	2017 Aug 15	4602-4616	Clin Cancer Res

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 some EGFR inhibitors in culture (PMID: 28424201), and therefore, is predicted to lead to 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 some EGFR inhibitors in cell culture (PMID: 28424201) and therefore, is predicted to lead to 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 some EGFR inhibitors in cell culture (PMID: 28424201), and therefore, is predicted to lead to 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 cell culture (PMID: 28424201), and therefore, is predicted to lead to 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 lead to 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 lead to 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 lead to a gain of Pik3ca protein function.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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 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
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 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 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 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