Aberrant MAPK Signaling Offers Therapeutic Potential for Treatment of Ovarian Carcinoma

Abstract

Ovarian cancer remains the most lethal gynecological malignancy worldwide due to lack of effective screening, vague early symptoms, poor description of biomarkers, and absence of effective treatment regimes. Epithelial ovarian carcinoma (EOC) is categorized into five distinct disease subtypes which collectively account for ~90% of ovarian carcinomas. Most women present at advanced stages contributing to a poor overall 5-year survival rate. Standard treatment for EOC is cytoreductive surgery and platinumbased chemotherapy; however, most patients suffer from recurrence and platinum-resistant disease, which highlights an urgent need for targeted therapy. The high frequency of molecular alterations affecting gain-of-function signaling through the RAS mitogenactivated protein kinase (MAPK) pathway in EOC has prompted pre-clinical and clinical efforts toward research into the effectiveness of MAPK pathway inhibition as a second-line treatment. The RAS/MAPK pathway is a highly conserved signal transduction cascade, often disrupted in cancer, that regulates tumorigenic phenotypes including cellular proliferation, survival, migration, apoptosis, and differentiation. Herein, the role of the MAPK pathway in EOC with emphasis on targetability of the pathway is described. Pre-clinical and clinical efforts to target MAPK signaling in EOC have identified several MAPK pathway inhibitors that offer efficacious potential for monotherapy and in combination with other compounds. Thus, inhibition of the RAS/MAPK pathway is emerging as a tractable strategy for treatment of ovarian cancer that may permit development of personalized therapy and improved prognosis for women challenged by this disease.

Construction and validation of molecular subtype and signature of immune cell‐related telomeric genes and prediction of prognosis and immunotherapy efficacy in ovarian cancer patients

“…Previous studies have indicated that the highly conserved MAPK signaling cascade is frequently disrupted and altered in various types of solid tumors. Additionally, inhibiting the RAS/MAPK pathway has emerged as a viable approach for OVC management 43 . Unsupervised clustering analysis was used to molecularly classify patients with OVC.…”

“…Additionally, inhibiting the RAS/MAPK pathway has emerged as a viable approach for OVC management. 43 Unsupervised clustering analysis was used to molecularly classify patients with OVC. Clustering was optimal when divided into two subtypes.…”

Highly expressed of BID indicates poor prognosis and mediates different tumor microenvironment characteristics in clear cell renal cell carcinoma

“…Wang et al [ 44 ] found that activating WNT signaling can promote cell growth and invasion of ccRCC. Colic et al [ 45 ] found that abnormal MAPK signaling transduction can provide therapeutic potential for the treatment of ovarian cancer. Li et al [ 46 ] also demonstrated that MAPK/ELK1 axis can regulate BCL6 and promote the occurrence of KRAS-driven lung cancer.…”

Differential molecular pathway expression according to chemotherapeutic response in ovarian clear cell carcinoma

“…The MAPK pathway is a highly conserved signal transduction cascade that is situated downstream of many growth factors receptors. Therefore, the MAPK pathway is activated by various stimuli, including peptide growth factors, cytokines, and hormones, among others, regulating cell proliferation, migration, apoptosis, and differentiation [ 54 ]. MAPK-related changes are most frequently discovered in the oncogene KRAS , which is overexpressed in 18% of OCCCs and mutated in 5–14% of cases [ 54 ].…”

“…Therefore, the MAPK pathway is activated by various stimuli, including peptide growth factors, cytokines, and hormones, among others, regulating cell proliferation, migration, apoptosis, and differentiation [ 54 ]. MAPK-related changes are most frequently discovered in the oncogene KRAS , which is overexpressed in 18% of OCCCs and mutated in 5–14% of cases [ 54 ]. Due to the high frequency of genetic changes via the MAPK pathway in OCCC, preclinical and clinical efforts have been directed toward investigating the efficacy of MAPK pathway inhibition as treatment.…”