Poster Presentation 38th Lorne Cancer Conference 2026

Evaluating PTEN mutations as a predictor of response to combinatorial therapy in ovarian cancer (#218)

Leean Miranda 1 , Carolina Lliberos 2 , Antonella Papa 1 2
  1. South Australian ImmunoGENomics and Cancer Institute, University of Adelaide, Adelaide, South Australia, Australia
  2. Cancer Program, Monash Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia

Ovarian cancer (OC) is one of the most prevalent gynaecological cancers with the highest mortality rate (1, 2). It has a poor prognosis with an average five-year survival rate of less than 50%, due to late diagnosis leading to chemotherapy resistance and high relapse rates (3-5).

Here, we investigated inhibitors that target the pro-survival PI3K pathway since its oncogenic activation has been linked to ovarian tumour formation. Although PI3K pathway inhibitors show limited efficacy as monotherapies, they have shown greater success in combination with other therapies (6-10). This includes polyadenosine diphosphate ribose polymerase (PARP)  inhibitors which cause synthetic lethality when homologous recombination is impaired, such as in the case of PI3K pathway inhibition (9).

We assessed mutations in the tumour suppressor PTEN as a potential predictor of response to combinatorial therapy with PI3K pathway and PARP inhibitors. Sensitivity to PARP inhibitors has been linked to PTEN mutations because not only does PTEN’s phosphatase activity inhibit PI3K pathway activation, but also PTEN contributes to maintaining genomic stability (11, 12). This association has been reported in endometrial and prostate cancers (13, 14). In OC, PTEN alterations occur in approximately 5% of cases across all histotypes (15, 16). Furthermore, loss of PTEN function contributes to the development of acquired therapy resistance (17).

We selected four OC cell lines (RMGI, SKOV3, TOV21G, IGROV1) based on the mutational status of PTEN and other OC associated genes (BRCA1, BRCA2, PIK3CA, TP53). Cell growth assays indicated that combinatorial therapies with the PARP inhibitor Olaparib, plus PI3K pathway inhibitors including PI3K inhibitor BYL-719 or AKT inhibitor MK-2206, were more efficacious than monotherapies in suppressing cell growth. Importantly, combinatorial therapy with BYL-719 demonstrated stronger effects than with MK-2206. However, single PTEN mutational status was not found to predict sensitivity to these combinatorial therapies in the selected cell lines.

To extend the relevance of our studies, we will next use patient-derived OC organoids, as a more physiological model. We will provide further evidence regarding the efficacy of PARP plus PI3K inhibition for OC treatment and aim to identify additional predictors of sensitivity.

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