Andrew Wu

Background: Pancreatic ductal adenocarcinoma (PDAC) is cancer that arises from the exocrine glands of the pancreas¹. It is highly lethal with a 5-year survival rate of less than 9%¹. It is expected to be the second leading cause of cancer-related deaths in the United States by 2030¹. A large barrier to effective treatment options is the drug resistance seen in PDAC. One of the prominent mechanisms of drug resistance that has been elucidated is the development of a unique desmoplastic stroma that grows around the PDAC tumor^1,2,3. This stroma serves as a physical barrier to entry of therapeutic compounds and creates a tumor microenvironment with signaling characteristics that are detrimental to the efficacy of immunotherapy¹. Targeting this stroma is a primary focus of current efforts to overcome PDAC drug resistance. A protein known as focal adhesion kinase (FAK) plays a critical role in the formation of the PDAC stroma and inhibiting this protein has shown promise in sensitizing PDAC to immunotherapy^1,2,3.

Objective: In this review, we determined the effectiveness of combining a FAK inhibitor with various PDAC therapies to assess the effect that stromal targeting has on enhancing PDAC immunotherapy.

Search Methods: A search in the PubMed database was conducted to find studies from 2024 to 2019 based on the following keywords: “pancreatic ductal adenocarcinoma”, “focal adhesion kinase”, “stroma“, “drug resistance”, “immunotherapy”.

Results: Our search found a study that demonstrated the depletion of the PDAC stroma when FAK was inhibited. The researchers then showed how tumor growth was slowed and overall survival of PDAC mouse models was improved when a FAK inhibitor was combined with immune checkpoint inhibitors in comparison to either therapy alone¹. We were also able to find studies that demonstrated a synergistic effect on overcoming drug resistance when FAK inhibition was combined with other anti-resistance strategies. Radiotherapy is a strategy employed in cancer to increase drug sensitivity but is ineffective in PDAC². When FAK was inhibited and stromal growth was depleted, radiotherapy was able to enhance the PDAC tumor’s sensitivity to immunotherapy². Another dual stromal targeting strategy employed was to combine FAK inhibition with an agent that would directly target the extracellular components of the stroma³. This had an enhanced effect on the reduction of the PDAC stroma and the PDAC tumor demonstrated increased sensitivity to immunotherapy³. Long-term FAK inhibition can unfortunately lead to its own resistance. This occurs through a STAT3/TGF-beta mediated mechanism, through which STAT3 becomes hyperactivated and leads to an uncontrolled, FAK-independent tumor growth⁴. FAK inhibitors have already begun to be tested in human clinical trials and lead to greater overall survival relative to current frontline treatment options⁵.

Conclusions: Targeting the stroma that surrounds the PDAC tumor is an effective method to sensitize the tumor to immunotherapy. One method of doing so is through the inhibition of focal adhesion kinase. Although combining FAK inhibition with immunotherapy is in the preliminary steps of human testing, this combination drug therapy is showing promise.

Works Cited:

1. Yamada T, Tateishi R, Iwai M, et al. Overcoming resistance of stroma-rich pancreatic cancer with focal adhesion kinase inhibitor combined with G47Δ and immune checkpoint inhibitors.Mol Ther Oncolytics. 2022;28:31-43. Published 2022 Dec 7. doi:10.1016/j.omto.2022.12.001
2. Lander VE, Belle JI, Kingston NL, et al. Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade.Cancer Discov. 2022;12(12):2774-2799. doi:10.1158/2159-8290.CD-22-0192
3. Blair AB, Wang J, Davelaar J, et al. Dual Stromal Targeting Sensitizes Pancreatic Adenocarcinoma for Anti-Programmed Cell Death Protein 1 Therapy.Gastroenterology. 2022;163(5):1267-1280.e7. doi:10.1053/j.gastro.2022.06.027
4. Jiang H, Liu X, Knolhoff BL, et al. Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion.Gut. 2020;69(1):122-132. doi:10.1136/gutjnl-2018-317424
5. Wang-Gillam A, Lim KH, McWilliams R, et al. Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study [published correction appears in Clin Cancer Res. 2023 Nov 14;29(22):4698]. Clin Cancer Res. 2022;28(24):5254-5262. doi:10.1158/1078-0432.CCR-22-0308