Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies. Cancer stem cells (CSCs), which are not targeted by current therapies, may be the reason for pronounced therapy resistance. A new treatment option in phase II trials is cabozantinib that inhibits the pancreatic CSC surface marker and tyrosine kinase receptor c-Met. The purpose of this study was to evaluate the effect of cabozantinib to stem-like features and therapy resistance. Established PDA cell lines, a gemcitabine-resistant subclone, non-malignant pancreatic ductal cells and primary spheroidal cultures from patient tumors were analyzed by MTT-assay, flow cytometry, colony and spheroid formation assays, western blotting, qRT-PCR, antibody protein array, immunohistochemistry and morphological features. Cabozantinib inhibited viability and spheroid formation and induced apoptosis in malignant cells with minor effects in non-malignant cells. After long-term cabozantinib treatment, PDA cells had altered anti- and pro-apoptotic signaling, but still responded to cabozantinib, as apoptosis only slightly decreased and viability only slightly increased suggesting a low resistance-inducing potential of cabozantinib. In parallel, c-Met expression and the pluripotency transcription factor SOX2 were downregulated, which might counteract development of full therapy resistance in long-term treated subclones. In single-treatment studies, cabozantinib increased efficacy of gemcitabine. Most importantly, cabozantinib strongly induced apoptosis and reduced viability in PDA cell lines, which are completely resistant toward gemcitabine. In primary, CSC-enriched spheroidal cultures cabozantinib downregulated CSC markers SOX2, c-Met and CD133 and induced apoptosis. These findings suggest that the clinical use of cabozantinib may be more effective than current chemotherapeutics.
Highlights
Cancer stem cells (CSCs) are made responsible for therapy resistance and progression, as this small subpopulation within the tumor mass is thought to survive conventional cytotoxic therapy due to defense and survival mechanisms.[5]
We show that the c-Met inhibitor cabozantinib targets stem cell-features in pancreatic cancer and thereby induces apoptosis and increases the efficacy of gemcitabine
We observed a shift to antiapoptotic signaling in response to 14 weeks of cabozantinib treatment, downregulation of CSC markers SOX2, CD133 and c-Met occurred in parallel and may prevent development of prounounced resistance
Summary
Cancer stem cells (CSCs) are made responsible for therapy resistance and progression, as this small subpopulation within the tumor mass is thought to survive conventional cytotoxic therapy due to defense and survival mechanisms.[5]. Cabozantinib is a potent dual inhibitor of c-Met and VEGFR-2 signaling.[12,15] Pre-clinical studies were performed in spontaneous pancreatic islet tumors in RIP-Tag[2] transgenic mice, where cabozantinib led to rapid, widespread and progressive regression of tumor vasculature, extensive hypoxia and apoptosis of tumor cells and decreased tumor aggressiveness.[15] In human pancreatic tumors growing orthotopically in NOD SCID mice, cabozantinib slowed tumor growth and reduced the population of CSCs when given alone or in combination with gemcitabine.[12] Administration of XL184 for 2 weeks after cardiac injection of pancreatic cancer cells prevented the development of metastases.[12] The clinical efficacy of cabozantinib in several progressed tumor entities is under investigation in randomized phase II studies, including patients with metastasizing pancreatic cancer.[16] On 29. Despite ongoing studies in patients, it is still completely unknown if cancer cells may develop extrinsic therapy resistance in response to cabozantinib treatment, as known for current cytotoxic therapies, and if cabozantinib might be able to overcome resistance to current cytotoxic therapy
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