Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients

Autor:	Thejaswini Gopalappa, Joon Young Hur, John N. Calley, Isabella H. Wulur, Jeeyun Lee, Philip J. Ebert, Steven M. Bray, Ruslan D. Novosiadly, Jiangang Liu, Melinda D. Willard, Seung Tae Kim, Amit Aggarwal, Young Suk Park, Swee Seong Wong, Hui Rong Qian, Joon Oh Park, Ho Yeong Lim, Hee Cheol Kim, Won Ki Kang, Christoph Reinhard, Jason C. Ting
Rok vydání:	2019
Předmět:	Adult Male Colorectal cancer Science Gene Dosage AKT1 Cetuximab medicine.disease_cause Predictive markers Article Cohort Studies Cell Line Tumor GNAS complex locus Cancer genomics Medicine Humans Amino Acid Sequence neoplasms PI3K/AKT/mTOR pathway EGFR inhibitors Aged Cancer Aged 80 and over Multidisciplinary biology Base Sequence business.industry Genomics Middle Aged medicine.disease digestive system diseases Gene Expression Regulation Neoplastic Treatment Outcome Drug Resistance Neoplasm Cancer research biology.protein Female KRAS Antibody business Colorectal Neoplasms medicine.drug
Zdroj:	Scientific Reports Scientific Reports, Vol 9, Iss 1, Pp 1-13 (2019)
ISSN:	2045-2322
Popis:	Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::de14fcfac08a919f8125f92abff8b706 https://pubmed.ncbi.nlm.nih.gov/31653970 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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