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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 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.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Bray SM,Lee J,Kim ST,Hur JY,Ebert PJ,Calley JN,Wulur IH,Gopalappa T,Wong SS,Qian HR,Ting JC,Liu J,Willard MD,Novosiadly RD,Park YS,Park JO,Lim HY,Kang WK,Aggarwal A,Kim HC,Reinhard C

doi

10.1038/s41598-019-51981-5

subject

Has Abstract

pub_date

2019-10-25 00:00:00

pages

15365

issue

1

issn

2045-2322

pii

10.1038/s41598-019-51981-5

journal_volume

9

pub_type

杂志文章

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