Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy
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Xiuting Liu1, John M Baer1, Meredith L Stone2
1Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
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.
Insights
Combining focal adhesion kinase (FAK) and RAF-MEK inhibitors overcomes resistance in pancreatic cancer. This dual inhibition, with chemotherapy, shows promise for treating KRAS-driven PDAC by improving antitumor immunity and survival.
Area of Science:
- Oncology
- Cancer Biology
- Immunotherapy
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with significant therapeutic resistance.
- The tumor microenvironment (TME) and KRAS mutations contribute to PDAC's resistance to therapies like MAPK inhibition.
- Focal adhesion kinase (FAK) inhibition can paradoxically lead to RAS/MAPK pathway hyperactivation in PDAC.
Purpose of the Study:
- To investigate the efficacy of combined FAK and RAF-MEK inhibition in PDAC.
- To elucidate the mechanisms by which the TME contributes to resistance against RAF-MEK inhibition.
- To evaluate the potential of combining FAK and RAF-MEK inhibitors with chemotherapy for PDAC treatment.
Main Methods:
- Utilized PDAC mouse models and patient tissues to study FAK inhibitor effects on the RAS/MAPK pathway.
- Administered combined FAK (VS-4718) and RAF-MEK (avutometinib) inhibitors to PDAC models.
- Assessed the role of cancer-associated fibroblasts (CAFs) in mediating resistance.
- Investigated the impact of combination therapy on tumor regression, metastasis, survival, and antitumor immunity.
Main Results:
- Concomitant FAK and RAF-MEK inhibition induced tumor growth inhibition and increased survival in PDAC models.
- CAFs were found to impede MYC downregulation by RAF-MEK inhibition, contributing to resistance.
- FAK inhibition reprogramed CAFs to reduce FGF1 production, overcoming RAF-MEK resistance.
- Adding chemotherapy to combined FAK and RAF-MEK inhibition led to tumor regression, reduced liver metastasis, and improved survival.
- Combination therapy enhanced antitumor immunity and T cell responses.
Conclusions:
- Combined FAK and RAF-MEK inhibition is a promising strategy for overcoming PDAC resistance.
- Targeting both cancer cells and the TME, particularly CAFs, is crucial for effective PDAC therapy.
- This combination therapy, especially with chemotherapy, warrants further clinical investigation for KRAS-driven PDAC.
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