Published OnlineFirst May 19, 2017; DOI: 10.1158/0008-5472.CAN-16-2675 Cancer Review Research TAM Receptor Tyrosine Kinases in Cancer Drug Resistance Mikaella Vouri and Sassan Hafizi Abstract Receptor tyrosine kinases (RTK) are major regulators of key spread, progression, and mortality, there is an increasing need for biological processes, including cell growth, survival, and differ- understanding the mechanisms by which cancer cells can evade entiation, and were established early on as proto-oncogenes, therapy-induced cell death. The TAM (Tyro3, Axl, Mer) subfamily with aberrant expression linked to tumor progression in many of RTKs in particular feature in a variety of cancer types that have cancers. Therefore, RTKs have emerged as major targets for selec- developed resistance to a broad range of therapeutic agents, tive therapy with small-molecule inhibitors. However, despite including both targeted as well as conventional chemotherapeu- improvements in survival rates, it is now apparent that the tics. This article reviews the roles of TAMs as tumor drivers and as targeting of RTKs with selective inhibitors is only transiently mediators of chemoresistance, and the potential effectiveness of effective, as the majority of patients eventually become resistant targeting them as part of therapeutic strategies to delay or combat to therapy. As chemoresistance is the leading cause of cancer resistance. Cancer Res; 77(11); 2775–8. Ó2017 AACR. Introduction and regulation of proinflammatory cytokine production (2, 3). MerTK is most distinctly recognized for its role in negative The TAM (Tyro3, Axl, MerTK) family of receptor tyrosine regulation of the immune system through its ability to mediate kinases (RTK) is defined by each member possessing an extracel- phagocytosis of apoptotic cells (4). Tyro3 has a more restricted lular combination of two immunoglobulin-like domains and two tissue expression profile and has been implicated in various roles, fibronectin type III repeats, a transmembrane portion, and an including myelination in the brain (5). intracellular region with intrinsic tyrosine kinase activity. The human TAM genes share similar genomic structures, and their resulting proteins share significant structural similarities, with The TAMs as Mediators of Chemoresistance greatest homology in the tyrosine kinase domain. The apparent Although the TAMs are not strong oncogenes, it is increas- molecular weights range from 100 to 140 kDa for Axl and Tyro3 ingly clear that their overexpression contributes to acquiring and 165 to 205 kDa for MerTK due to posttranslational modifica- resistance to both conventional as well as targeted chemother- tions, including glycosylation, phosphorylation, and ubiquitina- apeutics in both solid and blood cancers. Early observations tion. The established natural ligands for the TAMs are two homol- included increased Axl expression with resistance to the small ogous vitamin K–dependent proteins, Gas6 (all three TAMs), and molecule inhibitor imatinib (targets BCR-Abl, c-Kit, and protein S (Tyro3 and MerTK; ref. 1). PDGFR) in chronic myelogenous leukemia (CML; ref. 6) and to the chemotherapy drugs doxorubicin, VP16, and cisplatin TAM Functions in acute myeloid leukemia (7). Increased resistance to imatinib due to Axl and MerTK overexpression has also been reported in All three TAMs have transforming potential; however, Axl gastrointestinal stromal tumors (8) and non–smallcelllung overexpression has most frequently been detected in multiple carcinoma (NSCLC; ref. 9). cancers, and its role in supporting tumorigenesis is well recog- MerTK overexpression has been detected in high-grade glio- nized. Axl supports tumor growth and dissemination through blastomas and its knockdown to result in increased sensitivity to positive effects on cell survival, proliferation, migration, and etoposide while, conversely, control cells showed elevated MerTK invasion. Alongside these, Axl signaling is also involved in other activation upon DNA damage with increase resistance to etopo- processes ranging from the differentiation of cells in the erythroid side (10). Inhibition of Axl and MerTK also led to increased lineage, protecting blood vessels from injury, clearance of apo- chemosensitivity to temozolomide, carboplatin, and vincristine ptotic cells, angiogenesis, hematopoiesis, platelet aggregation, in astrocytoma (11), and to cisplatin and vincristine in neuro- blastoma (12). Axl was also shown to promote resistance to ALK inhibitors in neuroblastoma through induction of epithelial– Institute of Biomedical and Biomolecular Science, School of Pharmacy and mesenchymal transition (EMT; ref. 13). MerTK inhibition by an Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom. mAb was able to increase sensitivity to carboplatin in NSCLC due Corresponding Author: Sassan Hafizi, University of Portsmouth, St. Michael's to receptor internalization and subsequent degradation, which Building, White Swan Road, Portsmouth PO1 2DT, United Kingdom. Phone: led to STAT6, Akt, and ERK1/2 signaling inhibition (14). MerTK 4423-9284-2665; Fax: 4423-9284-3565; E-mail: sassan.hafi[email protected] was also shown in NSCLC to be essential for increased resistance doi: 10.1158/0008-5472.CAN-16-2675 to erlotinib through the regulation of MAPK and FAK signaling Ó2017 American Association for Cancer Research. pathways (15). www.aacrjournals.org 2775 Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst May 19, 2017; DOI: 10.1158/0008-5472.CAN-16-2675 Vouri and Hafizi Knockdown of Axl by short hairpin (sh)RNA has revealed Axl to identified as a marker for poor overall survival in ovarian cancer promote the survival of cutaneous squamous carcinoma cells (30). Also, galectin-3, a sugar-binding protein that has been through Akt activation and inhibition of the proapoptotic Bcl-2 implicated in cancer cell behaviors (31), was indicated to be a family proteins (16). Recently in melanoma, Tyro3 was shown novel ligand for MerTK (4). Axl expression has also been corre- to regulate the expression of microphthalmia-associated tran- lated with markers of DNA repair in different solid cancers; Axl scription factor, a master regulator of melanocyte development, inhibition induced reversal of EMT and decreased expression of and to promote tumorigenesis in spite of B-Raf–induced senes- DNA repair genes, rendering cancer cells sensitive to PARP inhi- cence (17). Tyro3 was also shown to promote cell proliferation bition in a synergistic manner (32). and chemoresistance in breast cancer (18). In addition, down- regulation of both Axl and Tyro3 was able to reverse taxol TAM Inhibition to Treat Tumor Drug resistance in ovarian cancer (19). Increased Axl expression has also been associated with acquired Resistance resistance to selective EGFR small-molecule inhibition. In lung In addition to their roles in primary tumorigenesis, the prev- cancers, this includes resistance to erlotinib through the induction alence of TAM receptors in patients displaying acquired drug- of an EMT-like state (20), as well as to gefitinib (21). In triple- resistant tumors renders the TAMs a viable target for therapies negative breast cancer cells, expression of Axl was identified as a against such evolved tumors. Importantly, TAM signaling inhibi- predictor for lack of response to lapatinib and erlotinib (22). tion sensitizes cells to chemotherapy, indicating that its effects are Targeting EGFR antibodies such as cetuximab has also led to multifaceted, and the aim of "shutting down" multiple key resistance in NSCLC and head and neck carcinomas through Axl biological processes in cancer cells can be achieved through a overexpression, via MAPK signaling (23). Such an association single target. A plethora of new, more specific, and higher affinity between EGFR and Axl molecular pathways also manifests itself targeting agents are currently under development (Table 1) that through hetero-interaction between EGFR and Axl molecules, may prove to be effective for preventing, delaying, or combating which can diversify downstream signaling pathways beyond tumor drug resistance. those triggered by EGFR alone (24). A recent example is from a study that showed Axl to be The prominent expression and functions of TAM receptors upregulated in CML patients that had developed resistance to across the immune system also suggests a potential role in BCR-Abl small-molecule inhibition, including through a T315I mediating resistance to immune checkpoint inhibitors in can- mutation in BCR-Abl. The selective Axl small-molecule inhibitor cer therapy. TAM receptors are notably expressed in many BGB324 inhibited the resistant CML cells independent of BCR- myeloid immune cells, including macrophages and dendritic Abl mutational status (33). This example indicates an efficacious cells (DC), and they may cooperate to create an immunosup- employment of Axl inhibition at the earliest signs of resistance pressive tumor microenvironment permissive to tumorigenesis development to first-line or targeted therapies. (25). MerTK is implicated in the suppression of the M1 mac- rophage proinflammatory cytokine response, and Axl is required for the termination of Toll-like receptor–dependent inflammatory response in DCs (25). Also, the TAMs have been Table 1. TAM-selective inhibitors currently in development shown to negatively regulate natural killer (NK) cell functional Name Target(s) Development stage maturation and normal expression of inhibitory