Dataset Information

ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer.

ABSTRACT: Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1A mutations may provide both an acquired and intrinsic mechanism of resistance to anti-EGFR therapies. We find that, ARID1A and EGFR-pathway genetic alterations are mutually exclusive across lung and colorectal cancers, further supporting a functional connection between these pathways. Our results not only suggest that ARID1A could be potentially used as a predictive biomarker for cetuximab treatment decisions but also provide a rationale for exploring therapeutic MAPK inhibition in an unexpected but genetically defined segment of CRC patients.

SUBMITTER: Johnson RM

PROVIDER: S-EPMC9482920 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer.

Johnson Radia M RM Qu Xueping X Lin Chu-Fang CF Huw Ling-Yuh LY Venkatanarayan Avinashnarayan A Sokol Ethan E Ou Fang-Shu FS Ihuegbu Nnamdi N Zill Oliver A OA Kabbarah Omar O Wang Lisa L Bourgon Richard R de Sousa E Melo Felipe F Bolen Chris C Daemen Anneleen A Venook Alan P AP Innocenti Federico F Lenz Heinz-Josef HJ Bais Carlos C

Nature communications 20220919 1

Most colorectal (CRC) tumors are dependent on EGFR/KRAS/BRAF/MAPK signaling activation. ARID1A is an epigenetic regulator mutated in approximately 5% of non-hypermutated CRC tumors. Here we show that anti-EGFR but not anti-VEGF treatment enriches for emerging ARID1A mutations in CRC patients. In addition, we find that patients with ARID1A mutations, at baseline, are associated with worse outcome when treated with cetuximab- but not bevacizumab-containing therapies; thus, this suggests that ARID1 ...[more]

PMID: 36117191

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Project description:BackgroundThe OPUS study demonstrated that addition of cetuximab to 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX4) significantly improved objective response and progression-free survival (PFS) in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer (mCRC). In patients with KRAS exon 2 mutations, a detrimental effect was seen upon addition of cetuximab to FOLFOX4. The current study reports outcomes in subgroups defined by extended RAS testing.Patients and methodsSamples from OPUS study KRAS exon 2 wild-type tumours were reanalysed for other RAS mutations in four additional KRAS codons (exons 3-4) and six NRAS codons (exons 2-4) using BEAMing. A cutoff of ⩾5% mutant/wild-type sequences was selected to define RAS status; we also report an analysis using a cutoff based on the technical lower limit for mutation identification (0.1%).ResultsOther RAS mutations were detected in 31/118 (26%) evaluable patients. In the extended analysis of RAS wild-type tumours (n=87), objective response was significantly improved by addition of cetuximab to FOLFOX4 (58% versus 29%; odds ratio 3.33 [95% confidence interval 1.36-8.17]; P=0.0084); although limited by population size, there also appeared to be trends favouring the cetuximab arm in terms of PFS and overall survival in the RAS wild-type group compared with the RAS evaluable group. There was no evidence that patients with other RAS mutations benefited from cetuximab, but small numbers precluded precise estimations of treatment effects. In the combined population of patients with any RAS mutation (KRAS exon 2 or other RAS), a clear detrimental effect was associated with addition of cetuximab to FOLFOX4.ConclusionPatients with RAS-mutant mCRC, as defined by mutations in KRAS and NRAS exons 2-4, derive no benefit and may be harmed by the addition of cetuximab to FOLFOX4. Restricting cetuximab administration to patients with RAS wild-type tumours will further tailor therapy to maximise benefit.

Dataset Information

ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer.

Publications

ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer.

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