Abstract C087: Window-of-opportunity trial of metastatic pancreatic cancer reveals mechanisms of response to targeting RAS signaling

Abstract

Abstract KRAS is mutated in ~85% of pancreatic ductal adenocarcinoma (PDAC) patients' 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, a 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). The clinical grade KI67 staining positivity was used as a readout of tumor response. We found three of 15 patients’ tumors had significantly decreased KI67 staining after MEKi treatment. Genomic sequence showed that two of three KI67-decreased patient’s tumors had KrasG12R mutations, which is significantly higher penetration compared to none of twelve KI67-non-responsive patient’s tumors. RNA-seq analysis showed that these KI67-decreased tumors are more classical-like compared to Ki67-non-responsive tumors. DSP analysis confirmed the downregulation of ERK phosphorylation after treatment in all examined cases. Moreover, MYC protein expression change is significantly correlated with KI67 protein expression change, which suggests MYC downregulation is the mechanism of action of MEK-inhibitor. Interestingly, MEK phosphorylation was upregulated after treatment in all examined cases. This suggests paradoxical RAF activation as a potential resistance mechanism. Furthermore, we found that Cobimetinib treatment changed the tumor microenvironment. Here, we summarize the multi-omics data and discuss the mechanism of response and resistance to target RAS signaling and related microenvironmental changes. Citation Format: Motoyuki Tsuda, Colin J. Daniel, Carl Pelz, Sam Sivagnanam, Dove Keith, Christopher L. Corless, Koei Chin, Lisa M. Coussens, Jonathan R. Brody, Charles D. Lopez, Gordon B. Mills, Rosalie C. Sears. Window-of-opportunity trial of metastatic pancreatic cancer reveals mechanisms of response to targeting RAS signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C087.