Acquired resistance to the PRMT5 inhibitor confers collateral sensitivity to MEK inhibition in MTAP-null non-small cell lung cancer

Fu, R.; Wang, Y.; Rehman, I.; Bedford, E.; Sharif, S.; Nguyen, N. D.; Powell, R. T.; Adams, A.; Liu, W.; Wang, S.; He, W.; Lu, Y.; Liu, B.; Shah, P. A.; Rodon Ahnert, J.; Chen, T.; Peng, W.; Stephan, C. C.; Liu, X.; Bedford, M. T.; Xu, H.

doi:10.64898/2026.04.16.719008

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bioRxiv · 10.64898/2026.04.16.719008

Acquired resistance to the PRMT5 inhibitor confers collateral sensitivity to MEK inhibition in MTAP-null non-small cell lung cancer

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Abstract

Protein arginine methyltransferase 5 (PRMT5) is a synthetic lethal target in methylthioadenosine phosphorylase-deleted (MTAP-null) cancers. Second-generation MTA-cooperative PRMT5 inhibitors preferentially target MTAP-null cells while largely sparing MTAP-wildtype (MTAP-WT) cells, thereby improving tumor selectivity over first-generation PRMT5 inhibitors. Despite encouraging efficacy and safety signals in early clinical studies, the modest objective response rates (ORRs) observed with these inhibitors suggest that intrinsic or acquired resistance may limit their clinical benefit. Here, we investigated mechanisms of acquired resistance to the MTA-cooperative PRMT5 inhibitor BMS-986504/MRTX1719 in MTAP-null non-small cell lung cancer (NSCLC) cells and sought to identify therapeutic vulnerabilities that emerge upon resistance. Using multiple in vitro-derived resistant models, we found that acquired resistance was not fully explained by alterations in PRMT5 activity or reduced MTA levels. Instead, resistance was associated with collateral sensitivity to MEK inhibition and enrichment of MAPK-related transcriptional programs. Together, these findings identify MEK inhibition as an actionable collateral vulnerability in MTAP-null NSCLC cells that acquire resistance to PRMT5 inhibition.

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Fu, R., Wang, Y., Rehman, I., Bedford, E., Sharif, S., Nguyen, N. D., Powell, R. T., Adams, A., Liu, W., Wang, S., He, W., Lu, Y., Liu, B., Shah, P. A., Rodon Ahnert, J., Chen, T., Peng, W., Stephan, C. C., Liu, X., Bedford, M. T., Xu, H.. 2026-04-21. Acquired resistance to the PRMT5 inhibitor confers collateral sensitivity to MEK inhibition in MTAP-null non-small cell lung cancer. https://doi.org/10.64898/2026.04.16.719008

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