Abstract C029: Window-of-opportunity trial of metastatic pancreatic cancer reveals potential mechanisms of response to targeting RAS/MEK signaling

Abstract KRAS is mutated in ∼85% of pancreatic ductal adenocarcinoma (PDAC) patient's tumors, suggesting that it is a key node of PDAC targeted therapy. RAF/MEK/ERK signaling is downstream of KRAS signaling. Preclinical studies targeting MEK showed promises but clinical trials failed to show the benefit compared to Standard-of-Care treatment chemotherapy. To elucidate the mechanism of action and resistance to several targeted therapies including MEK inhibition in human PDAC, we conducted a Window-Of-Opportunity trial for Metastatic pancreatic cancer (WOOM trial). In this trial, metastatic PDAC patients received 10 days of Cobimetinib, an FDA approved MEK inhibitor, therapy and specimens of pre- and post- treatment were obtained by biopsy to evaluate the response to targeted treatment using deep multi-omic analytics including DNA-seq, RNA-seq, multiplex IHC, cyclic IF and Digital Spatial Profiling (DSP). Four of 13 patient’s tumors were defined as Responsive tumors by using CA19- 9 and KI67 as a readout. Genomic sequence showed that KRAS amplifications were frequently seen in non-responsive tumors and KrasG12R mutations were seen with higher frequency in Responsive tumors. RNA-seq analysis showed that these Responsive tumors had lower KRAS activity and were more likely to be classical-like subtype compared to non-responsive tumors. DSP analysis confirmed the downregulation of ERK phosphorylation with paradoxical phospho- MEK activation after treatment in all examined cases which is consistent with effective target inhibition. Phospho-MYC protein expression and MYC transcriptomic activity were significantly decreased in responsive tumors, which suggest MYC downregulation could contribute to an active response to MEK inhibition. Single cell RNA-seq and spacial analysis showed tumor microenvironment changes after Cobimetinib treatment including the increase of CD8 T cell infiltration in responsive tumors. Furthermore, PDX from patient’s biopsy recapitulated patient's response to Cobimetinib and faithfully metastasized to the liver. Interestingly, Cobimetinib resistant PDX was also resistant to KRAS inhibitor. This model could be a great tool for testing new therapeutic strategies targeting the KRAS/MEK pathway. Here, we summarize the multi- omics data and discuss potential mechanisms of response and resistance to targeting KRAS signaling and related microenvironmental changes. Citation Format: Motoyuki Tsuda, Colin Daniel, Xiaoyan Wang, Carl Peltz, Hayley Zimmny, Alexander Smith, John Muschler, Xi Li, Tugba Yildiran Ozmen, Furkan Ozmen, Dove Keith, Christopher Corless, Koei Chin, Jonathan Brody, Charles Lopez, Gordon Mills, Rosalie Sears. Window-of-opportunity trial of metastatic pancreatic cancer reveals potential mechanisms of response to targeting RAS/MEK signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C029.