CRC Resistance to EGFR-Targeting Treatments Linked to Baseline, Acquired ARID1A Mutations

In Nature Communications, a team from Genentech, the University of Southern California Comprehensive Cancer Center, and elsewhere describe treatment resistance-related mutations in the epigenetic regulator gene ARID1A in colorectal cancer (CRC). The investigators turned to targeted circulating cell-free DNA sequencing to assess blood samples collected over time from up to 354 individuals with metastatic CRC before, during, and after treatment with chemotherapy in combination with the anti-EGFR treatment cetuximab or the anti-VEGF treatment bevacizumab. Their results suggest anti-EGFR treatment can select for ARID1A mutations in CRC — an effect not detected after anti-VEGF treatment. Along with these acquired mutations, the presence of pre-treatment mutations in ARID1A tended to coincide with poorer outcomes after anti-EGFR treatment. "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," the authors report. "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."