The footprint of kynurenine pathway in every cancer: a new target for chemotherapy

Treatment of cancers has always been a challenge for physicians. Typically, several groups of anti-cancer medications are needed for effective management of an invasive and metastatic cancer. Recently, therapeutic potentiation of immune system markedly improved treatment of cancers. Kynurenine pathway has an interwoven correlation with immune system. Kynurenine promotes T Reg (regulatory) differentiation, which leads to increased production of anti-inflammatory cytokines and suppression of cytotoxic activity of T cells. Overactivation of kynurenine pathway in cancers provides an immunologically susceptible microenvironment for mutant cells to survive and invade surrounding tissues. Interestingly, kynurenine pathway vigorously interacts with other molecular pathways involved in tumorigenesis. For instance, kynurenine pathway interacts with phospoinosisitide-3 kinase (PI3K), extracellular signal-regulated kinase (ERK), Wnt/β-catenin, P53, bridging integrator 1 (BIN-1), cyclooxygenase 2 (COX-2), cyclin-dependent kinase (CDK) and collagen type XII α1 chain (COL12A1). Overactivation of kynurenine pathway, particularly overactivation of indoleamine 2,3-dioxygenase (IDO) predicts poor prognosis of several cancers such as gastrointestinal cancers, gynecological cancers, hematologic malignancies, breast cancer, lung cancer, glioma, melanoma, prostate cancer and pancreatic cancer. Furthermore, kynurenine increases the invasion, metastasis and chemoresistance of cancer cells. Recently, IDO inhibitors entered clinical trials and successfully passed their safety tests and showed promising therapeutic efficacy for cancers such as melanoma, brain cancer, renal cell carcinoma, prostate cancer and pancreatic cancer. However, a phase III trial of epacadostat, an IDO inhibitor, could not increase the efficacy of treatment with pembrolizumab for melanoma. In this review the expanding knowledge towards kynurenine pathway and its application in each cancer is discussed separately.