The PI3K alpha inhibition sensitizes ovarian cancer with PIK3CA mutation to conventional chemotherapy

Peritoneal carcinomatosis in ovarian cancer is often associated with ascites where cancer cells grow as aggregates. Given the emerging evidence that multicellular growth enhances resistance to conventional therapies, and that patients frequently develop resistance to platinum salts, we investigated the efficiency of PI3K/Akt signalling pathway targeting in multicellular growth and its importance as a potential therapeutic target in cells resistant to platinum salts. Due to its importance in many cancers and to the frequent mutations of its encoding gene PIK3CA, we focused on targeting PI3Kα using BYL-719 (Alpelisib), an isoform-specific inhibitor already used in clinics. We used a panel of 3 ovarian cancer cell lines, SKOV-3, EFO-21 and OVCAR-3, which come from different histological origins and bear different mutations. PI3K targeting drugs inhibit the activity of the PI3K/Akt pathway in all tested ovarian cancer cell lines with a drastic reduction of the phosphorylation of Akt on the serine 473, regardless the histology or the mutational profile. We showed that when cultured in 3D aggregates, ovarian cancer cells are more resistant to the PI3Kα-specific inhibitor BYL-719 and cisplatin compared to 2D monolayers. BYL-719 synergizes with cisplatin in 3D cultures only in PIK3CAmutated SKOV-3 cells. This drug combination leads to a major cytotoxicity in 3D aggregates of this cell line. Finally, BYL-719 in combination with cisplatin remains active in 3D aggregates of SKOV-3 cells co-cultured with mesenchymal stem cells. We have identified a signalling pathway of interest for the treatment of advanced ovarian cancer in vitro, which could limit the progression of this disease. These data pave the road to investigate whether PI3Kα-specific inhibitor BYL-719 should be proposed in combination with cisplatin, in priority in patients bearing a PIK3CA mutation.

Figure A : The BYL-719 and cisplatin combination induces a synergistic cytotoxic effect in PIK3CA-mutated ovarian cancer cells SKOV-3 cultivated in 3D aggregates (matrix treatments and calculation of synergy by SynergyFinder).

Figure B : The BYL-719 and cisplatin combination induces a complete destruction of PIK3CA-mutated ovarian cancer cells SKOV-3 cultivated in 3D aggregates (living cells in green, dead cells in red).

Collaborations et partnerships

We thank the CRCT core technology platform, particularly Laetitia Ligat, for imaging and Marie Veronique Joubert for her help in MSC culture. Julie Guillermet Guibert’s laboratory is part of TOUCAN (Laboratoire d’Excellence, ANR), an integrated research programme on signal-targeted drug resistance. For this topic, Julie Guillermet Guibert’s laboratory received funding from the ARC (Foundation for Cancer Research) (ARCPGA2022120005630_6362), TOUCAN (Laboratoire d’Excellence, ANR), Fondation de France (Benoît Thibault’s salary), and Hôpitaux de Toulouse (Adrien Thole’s salary) and IUCT-Oncopole translational program (Cluster).