Dysregulated Cholesterol Metabolism with Anomalous PI3K/Akt/mTOR pathway Predicts Poor Carboplatin Response in High Grade Serous Ovarian Cancer

Abstract

ABSTRACTRapidly escalating High-Grade Serous Ovarian Cancer (HGSOC) incidences, relapse, and mortalities result from failed carboplatin therapy. In this regard, reprogrammed cholesterol metabolism arising from deregulated PI3K/Akt/mTOR signaling aggravates HGSOCs to evade carboplatin. Therefore, we designed a pilot study to ascertain their clinical relevance in determining the carboplatin response of HGSOC tumors.Non-NACT HGSOC (n=31) subjects were classified into optimum, borderline, and high cohorts based on blood cholesterol levels which positively correlated with their relative tissue cholesterol content. TCGA database showed that mutations in specific PI3K/Akt/mTOR candidates including cholesterol metabolism regulators (SREBP1, SREBP2, SRB-1, STAR, HMGCR) and prosurvival effectors (Akt, mTOR, p70S6K, P38MAPK, HIF-1α, COX2, VEGF) are characteristic to HGSOCs. We discerned dysregulations (expressions/activity) in SREBP2, SRB-1, STAR, and HMGCR along with Akt/pAktThr308, mTOR/pmTORSer2448, p70S6K, P38MAPK, HIF-1α, COX2, and VEGF proteins within high cohort. Herein, poorly differentiated tumors with escalated HMGCR activity overproduced cholesterol thereby rigidifying their cell membranes to restrain Pt-DNA adduct retention. With a carboplatin IC50of 5.23µM, high cohort tumors generated lesser drug-induced ROS and espoused unaltered mitochondrial-membrane depolarization and DNA damage profiles. These parameters were moderately altered in the borderline-HGSOC cohort possessing relatively less rigid membranes and a lower carboplatin IC50of 2.78µM. Accordingly, borderline and high cohorts were respectively denoted as intermediate responder and non-responder of carboplatin. On the contrary, the cholesterol-deficient optimum cohort (IC50-1.59µM) with fluid membranes was a carboplatin responder group.Our study established the candidature of abnormal cholesterol and PI3K/Akt/mTOR (protein-level) statuses as predictive markers to screen HGSOCs for carboplatin responses before therapy.