PIK3CA Mutations Contribute to Acquired Cetuximab Resistance in Patients with Metastatic Colorectal Cancer.

摘要: Purpose: Mutations in KRAS are considered to be the main drivers of acquired resistance epidermal growth factor receptor (EGFR) blockade patients with metastatic colorectal cancer (mCRC). However, potential role other genes downstream EGFR signaling pathway conferring has not been extensively investigated.Experimental Design: Using circulating tumor DNA (ctDNA) from mCRC and cetuximab resistance, we developed a targeted amplicon ultra-deep sequencing method screen for low-abundance somatic mutations panel that encode components pathway. significantly increased variant frequencies upon disease progression were selected by using quartile analysis. The functional consequences identified validated cultured cells.Results: We analyzed 32 development cohort. Of them, seven (22%) carried five novel PIK3CA mutations, whereas eight (25%) previously reported mutations. Functional studies showed (all exon 19; p.K944N, p.F930S, p.V955G, p.V955I, p.K966E) promote cell viability presence cetuximab. Only one mutation (p.K944N) was verified 27 validation cohort, simultaneous hotspot detected two patients. Among above 59 patients, those or RAS ctDNA pronounced decrease progression-free survival than no mutation.Conclusions: may potentially contribute mCRC. Clin Cancer Res; 23(16); 4602-16. ©2017 AACR.