Synthetic lethality guiding selection of drug combinations in ovarian cancer

Abstract

BackgroundSynthetic lethality describes a relationship between two genes where single loss of either gene does not trigger significant impact on cell viability, but simultaneous loss of both gene functions results in lethality. Targeting synthetic lethal interactions with drug combinations promises increased efficacy in tumor therapy.Materials and methodsWe established a set of synthetic lethal interactions using publicly available data from yeast screens which were mapped to their respective human orthologs using information from orthology databases. This set of experimental synthetic lethal interactions was complemented by a set of predicted synthetic lethal interactions based on a set of protein meta-data like e.g. molecular pathway assignment. Based on the combined set, we evaluated drug combinations used in late stage clinical development (clinical phase III and IV trials) or already in clinical use for ovarian cancer with respect to their effect on synthetic lethal interactions. We furthermore identified a set of drug combinations currently not being tested in late stage ovarian cancer clinical trials that however have impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.ResultsTwelve of the tested drug combinations addressed a synthetic lethal interaction with the anti-VEGF inhibitor bevacizumab in combination with paclitaxel being the most studied drug combination addressing the synthetic lethal pair between VEGFA and BCL2. The set of 84 predicted drug combinations for example holds the combination of the PARP inhibitor olaparib and paclitaxel, which showed efficacy in phase II clinical studies.ConclusionA set of drug combinations currently not tested in late stage ovarian cancer clinical trials was identified having impact on synthetic lethal interactions thus being worth of further investigations regarding their therapeutic potential in ovarian cancer.

Highlights in Resistance Mechanism Pathways for Combination Therapy

“…Another promising example of the capabilities of synthetic lethality screening has been published for late ovarian cancer; the authors proposed a list of 84 new drug combinations to be tested in preclinical and clinical trials [184].…”

SynLethDB 2.0: A web-based knowledge graph database on synthetic lethality for novel anticancer drug discovery

“…By inhibiting the SL partner of a gene with cancer-specific alteration, we can kill cancer cells and spare normal cells, thereby reducing the side effect of the treatment [24, 23]. To discover SL gene pairs as a gold mine of cancer drug targets, researchers have applied various techniques, including chemical screening [16], RNAi screening [11, 1, 5, 29, 2], CRISPR screening [14, 39] and bioinformatics methods [22, 25, 41, 49].…”

Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden

“…Though paclitaxel has been extensively applied to treat advanced EOC, this drug has severe side effects, and cases frequently have adaptive chemoresistance and consequent tumour recurrence. However, paclitaxel has shown synergistic interaction with various classes of targeted therapeutic agents (eg anti‐VEGF inhibitors and PARP inhibitors) and is currently being assessed in adjuvant and neo‐adjuvant treatment settings for ovarian cancer . Interestingly, BBI608 can enhance paclitaxel sensitivity in A2780 and SKOV3 cells at a low concentration of 1nM in a synergistical manner.…”