MerTK inhibition by UNC569 triggers DNA damage and JNK/p38 MAPK cascade-driven apoptosis in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with increasing mortality rates and remains a major clinical challenge due to its aggressive progression and limited therapeutic options. Therefore, the identification of early biomarkers and the development of effective targeted therapies are critically needed. MerTK, a receptor tyrosine kinase aberrantly expressed in various cancers, can be selectively inhibited by UNC569, a small-molecule antagonist with demonstrated efficacy in hematologic malignancies. This study shows that UNC569 potently suppresses PDAC cell proliferation and clonogenic growth, inhibits migration and invasion by attenuating epithelial-mesenchymal transition, and enhances the sensitivity of PDAC cells to Gemcitabine while promoting apoptosis. Mechanistically, UNC569 induces DNA damage-mediated G2/M phase arrest and activates JNK/p38 mitogen-activated protein kinase-dependent apoptotic signaling. Collectively, these results establish MerTK as a promising therapeutic target in PDAC and highlight the translational potential of UNC569 as a dual-pathway inhibitor for PDAC treatment.

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy, ranked as the seventh leading cause of global cancer mortality in 2020 [1]. Both its incidence and mortality rates continue to rise, and projections suggest that PDAC may become the second leading cause of cancer-related deaths by 2030 [2]. In China, clinical outcomes are particularly dismal: the majority of patients are diagnosed at an advanced-stage, with a median overall survival of less than 7.8 months and 5-year survival rates barely exceeding 10% [3]. Given the substantial toxicity and limited efficacy of current chemotherapeutics regimens, surgical resection remains the primary curative option. Consequently, the identification of novel therapeutic targets and the development of safe and effective agents are urgently required to improve PDAC prognosis.

The receptor tyrosine kinase MerTK plays a pivotal role in maintaining tissue homeostasis and innate immunity. It is overexpressed in a wide range of malignancies including melanoma [4], lung cancer [5], glioblastoma [6,7], hepatic [8], gastric carcinomas [9], as well as hematologic tumors. Emerging evidence highlights a critical role for MerTK and other members of the TAM family receptor in driving the initiation and progression of PDAC [10]. MerTK-targeting monoclonal antibodies have been shown to induce apoptosis in triple-negative breast cancer [11], establishing MerTK as a promising therapeutic target. Several small-molecule MerTK inhibitors (e.g., UNC569, UNC1062, UNC1666, UNC2025, and UNC2250) have demonstrated potent anti-tumor efficacy in preclinical models [12–16]. UNC569, a highly selective MerTK inhibitor, binds to the adenine pocket of MerTK to prevent its phosphorylation [12], exhibiting robust activity against acute lymphoblastic leukemia in vitro and in vivo. Furthermore, MerTK contributes to chemotherapy resistance by enhancing pro-survival signaling pathways and facilitating tumor immune evasion [17]. For example, the MerTK ligand Gas6 activates oncogenic signaling in Osimertinib-treated EGFR mutation non-small cell lung cancer (NSCLC) [18], whereas in PD-1/PD-L1-resistant hepatocellular carcinoma (HCC), MerTK upregulates SLC7A11 via the ERK/SP1 pathway to inhibit ferroptosis and concurrently recruits myeloid-derived suppressor cells (MDSCs), thereby fostering an immunosuppressive tumor microenvironment (TME) [19]. Despite these advances, the molecular mechanisms underlying resistance to MerTK-targeted small-molecule inhibitors remain poorly understood, thereby limiting their clinical translation.