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HOME  SCIENCE TRANSLATIONAL MEDICINE  VOL. 16, NO. 770  STROMAL REPROGRAMMING OVERCOMES RESISTANCE TO RAS-MAPK INHIBITION TO IMPROVE PANCREAS CANCE…

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Stromal reprogramming overcomes resistance to RAS-MAPK inhibi-
tion to improve pancreas cancer responses to cytotoxic and immune
therapy
XIUTING LIU
, JOHN M. BAER, [...], AND DAVID G. DENARDO  +18 authors Authors Info & Affiliations

SCIENCE TRANSLATIONAL MEDICINE 23 Oct 2024 Vol 16, Issue 770 DOI: 10.1126/scitranslmed.ado2402

315
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Editor’s summary

Pancreatic ductal adenocarcinoma (PDAC) often becomes resistant to therapy. It is unclear how combining dif-
ferent 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) inhi-
bition improved survival and inhibited tumor growth in mouse PDAC models. Sequencing and cell culture ex-
periments 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 target-
ing both stromal and tumor factors involved in therapy resistance could improve PDAC responses to treatment.
—Brandon Berry

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 ki-
nase (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 chemo-
therapy 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.

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Supplementary Materials
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Materials and methods

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REFERENCES AND NOTES

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4 L. Dennison, A. Ruggieri, A. Mohan, J. Leatherman, K. Cruz, S. Woolman, N. Azad, G. B. Lesinski, E. M. Jaffee, M. Yarchoan, Context-dependent im-
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