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.
Show 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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