Figure 1. Downstream of MERTK. According to a study in The Journal of Clinical Investigation, inhibiting c-Mer proto-oncogene tyrosine kinase (MERTK)-which lies upstream from BRAF-could help treat melanoma.

In melanoma tumor cells [a], overexpression of MERTK activates multiple signaling pathways. Activated Ras [b(1)] signals through BRAF, CRAF (RAF1) and other Raf proteins to activate MAP kinase kinase 1 (MAP2K1; MEK1) and MEK2 (MAP2K2). Activated JAK kinases (JAKs) [b(2)] in turn activate signal transducer and activator of transcription (STAT) proteins. Activated phosphoinositide 3-kinase (PI3K) [b(3)] induces activation of protein kinase B (PKB; PKBA; AKT; AKT1). Upregulation of any or all of these three pathways leads to melanoma growth, proliferation and survival [c].

Additionally, expression of MERTK on tumor-infiltrating macrophages [d] may enhance their ability to engulf and clear apoptotic tumor cells [e], thereby leading to reduced immune system responses [f] and enhanced tumor survival.

Multiple companies market or are developing products that inhibit proteins in pathways [b(1)]-[b(3)] to treat melanoma.

CEP-32496, a dual inhibitor of BRAF and epidermal growth factor receptor (EGFR) from Ambit Biosciences Corp. and Teva Pharmaceutical Industries Ltd., is in preclinical testing to treat melanoma.

DP-4978, an oral small molecule dual inhibitor of mutant BRAF and CRAF from Deciphera Pharmaceuticals LLC and Eli Lilly and Co., is in preclinical testing to treat melanoma.

Nanolipolee 007, an i.v. nanoparticle formulation containing leelamine derived from the bark of a pine tree that inhibits protein kinase Bg (PKBG; AKT3) and STAT3, is in preclinical testing from Melanovus Oncology Inc. to treat melanoma.