1. Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy.
- Author
-
Liu, Xiuting, Baer, John M., Stone, Meredith L., Knolhoff, Brett L., Hogg, Graham D., Turner, Madeleine C., Kao, Yu-Lan, Weinstein, Alyssa G., Ahmad, Faiz, Chen, Jie, Schmidt, Andrew D., Klomp, Jeffrey A., Coho, Heather, Coho, Kayjana S., Coma, Silvia, Pachter, Jonathan A., Bryant, Kirsten L., Kang, Liang-I, Lim, Kian-Huat, and Beatty, Gregory L.
- Subjects
FOCAL adhesion kinase ,MITOGEN-activated protein kinases ,PANCREATIC duct ,PANCREATIC cancer ,TUMOR growth ,PACLITAXEL - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is often resistant to therapy. An immune suppressive tumor microenvironment (TME) and oncogenic mutations in KRAS have both been implicated as drivers of resistance to therapy. Mitogen-activated protein kinase (MAPK) inhibition has not yet shown clinical efficacy, likely because of rapid acquisition of tumor-intrinsic resistance. However, the unique PDAC TME may also be a driver of resistance. We found that long-term focal adhesion kinase (FAK) inhibitor treatment led to hyperactivation of the RAS/MAPK pathway in PDAC cells in mouse models and tissues from patients with PDAC. Concomitant inhibition of both FAK (with VS-4718) and rapidly accelerated fibrosarcoma and MAPK kinase (RAF-MEK) (with avutometinib) induced tumor growth inhibition and increased survival across multiple PDAC mouse models. In the TME, cancer-associated fibroblasts (CAFs) impaired the down-regulation of MYC by RAF-MEK inhibition in PDAC cells, resulting in resistance. By contrast, FAK inhibition reprogramed CAFs to suppress the production of FGF1, which can drive resistance to RAF-MEK inhibition. The addition of chemotherapy to combined FAK and RAF-MEK inhibition led to tumor regression, a decrease in liver metastasis, and improved survival in KRAS-driven PDAC mouse models. Combination of FAK and RAF-MEK inhibition alone improved antitumor immunity and priming of T cell responses in response to chemotherapy. These findings provided the rationale for an ongoing clinical trial evaluating the efficacy of avutometinib and defactinib in combination with gemcitabine and nab-paclitaxel in patients with PDAC and may suggest further paths for combined stromal and tumor-targeting therapies. Editor's summary: Pancreatic ductal adenocarcinoma (PDAC) often becomes resistant to therapy. It is unclear how combining different therapies could overcome tumor resistance. Liu et al. showed that combining focal adhesion kinase (FAK) inhibition with rapidly accelerated fibrosarcoma and mitogen-activated protein kinase kinase (RAF-MEK) inhibition improved survival and inhibited tumor growth in mouse PDAC models. Sequencing and cell culture experiments confirmed that cancer-associated fibroblasts in the tumor microenvironment were responsible for therapy resistance. Combining FAK and RAF-MEK inhibition with chemotherapy resulted in tumor regression, increased survival, and decreased liver metastasis in mouse models. Together, these results suggest that targeting both stromal and tumor factors involved in therapy resistance could improve PDAC responses to treatment. —Brandon Berry [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF