Molecular Pathways: MERTK Signaling in Cancer

Abstract

MERTK is a receptor tyrosine kinase of the TAM (Tyro3, Axl, MERTK) family, with a defined spectrum of normal expression. However, MERTK is overexpressed or ectopically expressed in a wide variety of cancers, including leukemia, non-small cell lung cancer, glioblastoma, melanoma, prostate cancer, breast cancer, colon cancer, gastric cancer, pituitary adenomas, and rhabdomyosarcomas, potentially resulting in the activation of several canonical oncogenic signaling pathways. These include the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways, as well as regulation of signal transducer and activator of transcription family members, migration-associated proteins including the focal adhesion kinase and myosin light chain 2, and prosurvival proteins such as survivin and Bcl-2. Each has been implicated in MERTK physiologic and oncogenic functions. In neoplastic cells, these signaling events result in functional phenotypes such as decreased apoptosis, increased migration, chemoresistance, increased colony formation, and increased tumor formation in murine models. Conversely, MERTK inhibition by genetic or pharmacologic means can reverse these pro-oncogenic phenotypes. Multiple therapeutic approaches to MERTK inhibition are currently in development, including ligand "traps", a monoclonal antibody, and small-molecule tyrosine kinase inhibitors.

Mer tyrosine kinase promotes the survival of t(1;19)-positive acute lymphoblastic leukemia (ALL) in the central nervous system (CNS)

“…2,11 Linger et al 12 reported that Mer is overexpressed on pre-B-cell ALL (B-ALL) cells of pediatric patients with t(1;19)(q23;p13) translocation. Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts.…”

“…[1][2][3] The TAM receptor family consists of Tyro3, Axl, and Mer 4 which all have been found to have transforming properties. [5][6][7] Mer expression has been shown on macrophages, natural killer (NK) cells, dendritic cells, megakaryocytes, and platelets, 8 but it is not known to be present on normal T and B lymphocytes at any stage of differentiation.…”

“…10 Studies overexpressing Mer in fibroblasts found that it can induce extracellular signalregulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, nuclear factor-kB (NF-kB) and enhance cell survival via phosphatidylinositol 3-kinase (PI3K)/AKT. 2,11 Linger et al 12 reported that Mer is overexpressed on pre-B-cell ALL (B-ALL) cells of pediatric patients with t(1;19)(q23;p13) translocation. Furthermore, inhibition of Mer by RNA interference (RNAi) reduced survival and chemoresistance of pre-B-ALL cell lines and prolonged survival of xenografts.…”

The impact of prior malignancies on second malignancies and survival in MM patients: a population-based study

“…In addition, studies have found the same oncogenic mutations in both MM and melanoma. 19,32,33,41 We found an association between prior malignancy and the development of respiratory malignancies in MM patients. To our knowledge, MM patients have not been found to have increased risk of developing respiratory malignancies; on the contrary, data from the Surveillance, Epidemiology, and End Results database suggest reduced incidence in MM patients.…”

“…1 These studies have a small number of patients that developed second malignancies, 49 and 59 patients, respectively. Underlying explanation for our findings, that a prior malignancy increases the risk of second malignancies in MM patients, could include genetic susceptibilities, [17][18][19][20][21][22][32][33][34][35] immunosuppression, [36][37][38] and therapy-related cancers. 12,13,39 We found MM patients with a prior cancer diagnosis to have an increased risk of developing hematological malignancy, melanoma, nonmelanoma skin cancer, and respiratory malignancy compared with MM patients who did not.…”