Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

Woolston, A.; Khan, K.; Spain, G.; Barber, L. J.; Griffiths, B.; Gonzalez Exposito, R.; Patil, Y.; Mansukhani, S.; Davies, M. N.; Furness, A.; Sclafani, F.; Peckitt, C.; Kouvelakis, K.; Ranftl, R.; Begum, R.; Rana, I.; Thomas, J.; Bryant, A.; Quezada, S.; Wotherspoon, A.; Khan, N.; Fotiadis, N.; Marafioti, T.; Powles, T.; Calvo, F.; Guettler, S.; von Loga, K.; Rao, S.; Watkins, D.; Starling, N.; Chau, I.; Sadanandam, A.; Cunningham, D.; Gerlinger, M.

doi:10.1101/448076

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bioRxiv · 10.1101/448076

Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer

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Abstract

Anti-epidermal growth factor receptor (EGFR) antibodies (anti-EGFR-Ab) are effective in a subgroup of patients with metastatic colorectal cancer (CRC). We applied genomic and transcriptomic analyses to biopsies from 35 RAS wild-type CRCs treated with the anti-EGFR-Ab cetuximab in a prospective trial to interrogate the molecular resistance landscape. This validated transcriptomic CRC-subtypes as predictors of cetuximab benefit; identified novel associations of NF1-inactivation and non-canonical RAS/RAF-aberrations with primary progression; and of FGF10- and non-canonical BRAF-aberrations with AR. No genetic resistance drivers were detected in 64% of AR biopsies. The majority of these had switched from the cetuximab-sensitive CMS2-subtype pretreatment to the fibroblast- and growth factor-rich CMS4-subtype at progression. Fibroblast supernatant conferred cetuximab resistance in vitro, together supporting subtype-switching as a novel mechanism of AR. Cytotoxic immune infiltrates and immune-checkpoint expression increased following cetuximab responses, potentially providing opportunities to treat CRCs with molecularly heterogeneous AR with immunotherapy.

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Woolston, A., Khan, K., Spain, G., Barber, L. J., Griffiths, B., Gonzalez Exposito, R., Patil, Y., Mansukhani, S., Davies, M. N., Furness, A., Sclafani, F., Peckitt, C., Kouvelakis, K., Ranftl, R., Begum, R., Rana, I., Thomas, J., Bryant, A., Quezada, S., Wotherspoon, A., Khan, N., Fotiadis, N., Marafioti, T., Powles, T., Calvo, F., Guettler, S., von Loga, K., Rao, S., Watkins, D., Starling, N., Chau, I., Sadanandam, A., Cunningham, D., Gerlinger, M.. 2018-10-19. Genomic and transcriptomic determinants of therapy resistance and immune landscape evolution during anti-EGFR treatment in colorectal cancer. https://doi.org/10.1101/448076

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