Targeting TAM to Tame Pancreatic Cancer
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Targeting TAM to Tame Pancreatic Cancer Mitchell S. von Itzstein1,2 · Michael C. Burke1,2 · Rolf A. Brekken3 · Todd A. Aguilera4 · Herbert J. Zeh3 · Muhammad Shaalan Beg1,2
© Springer Nature Switzerland AG 2020
Abstract Pancreatic cancer is expected to become the second leading cause of cancer-related death within the next few years. Current therapeutic strategies have limited effectiveness and therefore there is an urgency to develop novel effective therapies. The receptor tyrosine kinase subfamily TAM (Tyro3, Axl, MerTK) is directly implicated in the pathogenesis of the metastatic, chemoresistant, and immunosuppressive phenotype in pancreatic cancer. TAM inhibitors are promising investigational therapies for pancreatic cancer due to their potential to target multiple aspects of pancreatic cancer biology. Specifically, recent mechanistic investigations and therapeutic combinations in the preclinical setting suggest that TAM inhibition with chemotherapy, targeted therapy, and immunotherapy should be evaluated clinically.
Key Points
1 Introduction
The TAM receptor tyrosine kinase signaling pathway is implicated in the pathophysiology of pancreatic cancer.
Pancreatic cancer is expected to become the second leading cause of cancer related death within the USA in the next few years [1]. Unfortunately, there is no screening test for pancreatic cancer and patients are most commonly diagnosed with advanced disease [2, 3]. Current standard-of-care treatment for metastatic pancreatic cancer includes conventional cytotoxic chemotherapy with 5-fluorouracil-based treatment (e.g., Folfirinox) or gemcitabine-based treatment, which achieve at best modest responses [4]. The recent approval of olaparib represented the first biomarker-specific approval for pancreatic cancer for patients harboring germline BRCA mutations [5]. Advances in the understanding of pancreatic cancer biology should allow for the development of further targeted therapies. The TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases (RTKs) are involved in immune, vascular, reproductive, hematopoietic, and nervous system functions [6]. The TAM receptors are composed of an extracellular ligandbinding domain, a transmembrane domain, and a conserved cytoplasmic tyrosine kinase domain that is responsible for intracellular signaling [7, 8]. The control of TAM expression is not fully understood and may differ for each TAM member. The most well studied is Axl, the expression of which is positively regulated by numerous endogenous signaling molecules known to bind to the Axl promoter region, including HIF, SP-1/3, AP-1/2, MZF-1, and YAP/TAZ/TEAD [8–19].
Preclinical models demonstrate that pharmacological inhibition of TAM signaling has activity against pancreatic cancer and should be clinically evaluated.
* Muhammad Shaalan Beg [email protected] 1
Division of Hematology/Oncology, Department of Internal Medicine, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390‑8852, USA
2
Division of Hemato
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