Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients
Abstract 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...
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Nature Portfolio
2019
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oai:doaj.org-article:f456fa8deb9947ea89d5b6e8de43eb832021-12-02T15:08:09ZGenomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients10.1038/s41598-019-51981-52045-2322https://doaj.org/article/f456fa8deb9947ea89d5b6e8de43eb832019-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-51981-5https://doaj.org/toc/2045-2322Abstract 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.Steven M. BrayJeeyun LeeSeung Tae KimJoon Young HurPhilip J. EbertJohn N. CalleyIsabella H. WulurThejaswini GopalappaSwee Seong WongHui-Rong QianJason C. TingJiangang LiuMelinda D. WillardRuslan D. NovosiadlyYoung Suk ParkJoon Oh ParkHo Yeong LimWon Ki KangAmit AggarwalHee Cheol KimChristoph ReinhardNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-13 (2019) |
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Medicine R Science Q Steven M. Bray Jeeyun Lee Seung Tae Kim Joon Young Hur Philip J. Ebert John N. Calley Isabella H. Wulur Thejaswini Gopalappa Swee Seong Wong Hui-Rong Qian Jason C. Ting Jiangang Liu Melinda D. Willard Ruslan D. Novosiadly Young Suk Park Joon Oh Park Ho Yeong Lim Won Ki Kang Amit Aggarwal Hee Cheol Kim Christoph Reinhard Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients |
| description |
Abstract 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. |
| format |
article |
| author |
Steven M. Bray Jeeyun Lee Seung Tae Kim Joon Young Hur Philip J. Ebert John N. Calley Isabella H. Wulur Thejaswini Gopalappa Swee Seong Wong Hui-Rong Qian Jason C. Ting Jiangang Liu Melinda D. Willard Ruslan D. Novosiadly Young Suk Park Joon Oh Park Ho Yeong Lim Won Ki Kang Amit Aggarwal Hee Cheol Kim Christoph Reinhard |
| author_facet |
Steven M. Bray Jeeyun Lee Seung Tae Kim Joon Young Hur Philip J. Ebert John N. Calley Isabella H. Wulur Thejaswini Gopalappa Swee Seong Wong Hui-Rong Qian Jason C. Ting Jiangang Liu Melinda D. Willard Ruslan D. Novosiadly Young Suk Park Joon Oh Park Ho Yeong Lim Won Ki Kang Amit Aggarwal Hee Cheol Kim Christoph Reinhard |
| author_sort |
Steven M. Bray |
| title |
Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients |
| title_short |
Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients |
| title_full |
Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients |
| title_fullStr |
Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients |
| title_full_unstemmed |
Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients |
| title_sort |
genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients |
| publisher |
Nature Portfolio |
| publishDate |
2019 |
| url |
https://doaj.org/article/f456fa8deb9947ea89d5b6e8de43eb83 |
| work_keys_str_mv |
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| _version_ |
1718388292693524480 |