A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

Tsuda, M.; Keith, D.; Daniel, C. J.; Pelz, C.; Blise, K. E.; Ozmen, T. Y.; Ozmen, F.; Hawthone, K.; Eng, J. R.; Li, X.; Wang, X.; Zimny, H.; Sivagnanam, S.; Betre, K.; Kirchberger, N.; Chong, B.; Lee, J.; Matter, _.; Smith, A.; Agritelley, E. S.; Waugh, T.; Sannecy, A.; Alarcon, K.; Youm, I.; Protzek, S.; Egger, J.; English, I. A.; Yang, M.; Shah, V. M.; Link, J. M.; Creason, A. L.; Worth, P. J.; Goodyear, S. M.; Chin, K.; Muschler, J. L.; Suciu, C. G.; Corless, C. L.; Cao, S.; Soucek, L.; Kardosh, A.; Coussens, L. M.; Brody, J. R.; Lopez, C. D.; Mills, G. B.; Sears, R. C.

doi:10.64898/2025.12.12.693851

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bioRxiv · 10.64898/2025.12.12.693851

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway

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Abstract

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS/MYC co-gain and KRASG12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRASG12D/MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRASG12D/MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

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Tsuda, M., Keith, D., Daniel, C. J., Pelz, C., Blise, K. E., Ozmen, T. Y., Ozmen, F., Hawthone, K., Eng, J. R., Li, X., Wang, X., Zimny, H., Sivagnanam, S., Betre, K., Kirchberger, N., Chong, B., Lee, J., Matter, _., Smith, A., Agritelley, E. S., Waugh, T., Sannecy, A., Alarcon, K., Youm, I., Protzek, S., Egger, J., English, I. A., Yang, M., Shah, V. M., Link, J. M., Creason, A. L., Worth, P. J., Goodyear, S. M., Chin, K., Muschler, J. L., Suciu, C. G., Corless, C. L., Cao, S., Soucek, L., Kardosh, A., Coussens, L. M., Brody, J. R., Lopez, C. D., Mills, G. B., Sears, R. C.. 2025-12-15. A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway. https://doi.org/10.64898/2025.12.12.693851

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