Chemoresistance and targeting of growth factors/cytokines signalling pathways: towards the development of effective therapeutic strategy for endometrial cancer.

Endometrial cancer tends to be an aggressive malignancy. Although the disease prognosis can be good at the early stages of disease, the advanced condition is not curable. Chemotherapy regimens and hormone-based therapy in combination with surgery are major approaches for the management of endometrial cancers. However, intrinsic chemoresistance reduces the success rate and increases the possibility of disease relapse. Investigation of underlying mechanisms revealed altered activation of PI3K/AKT, MAPK, fibroblast growth factor (FGF), mTOR and WNT pathways and reduced gene expression of tumor suppressor p53 in recurrent endometrial cancer. A PTEN mutation, deletion or degradation induces positive p-AKT expression, while PI3K knock-down increases the level of pro-apoptotic proteins and decreases the level of anti-apoptotic ones in cancerous cells. Additionally, RAS proteins trigger both the RAF-MEK-ERK and PI3K-PTEN-AKT signalling mechanisms, thus conferring resistance to anti-tumor agents. FGF up-regulates angiogenesis via receptor-mediated tyrosine kinase activation. Single nucleotide polymorphism, gene amplification or missense mutations of FGFR2 are associated with endometrial cancer. The mTOR complex integrates the nutrient and mitogen signals via AMPKs, S6 kinase 1 (S6K1) and eukaryotic initiation factors, causing unrestricted endometrial cellular proliferation. WNT signalling molecules, such as frizzled receptors, β-catenin, PORCN, RSPO3 and DKK1 undergo dysregulation, and drugs targeting these pathways are under clinical trials in patients with endometrial cancer. Common therapies for endometrial tumor include platinum-based anti-neoplastics, taxanes, nucleoside analogues, immune modulators, FGFR and tyrosine kinase inhibitors, small-molecule mTOR inhibitors and drugs that trigger cell cycle arrest in the G1 phase. Taken together, the current review elucidates the mechanism underlying endometrial cancer, existing therapies and chemoresistance, and points towards the need for novel therapeutics that may promote disease-free survival.