Evaluating the clinical utility of apitolisib/ vorinostat combination in apitolisib-resistant H1975 lung adenocarcinoma

Abstract

Background: The PI3K signalling pathway regulates the metabolic activity of cells. Disruption by PI3K inhibitors causes an aerobic/anaerobic imbalance that decreases energy production and cell growth. Cancer cells adapt to PI3K inhibitors in order to reduce their effectiveness. Resistance to apitolisib could be due to intrinsic factors or acquired adaptation. Oncologists often ask whether to discontinue apitolisib, increase its dose, or use a drug combination. Methods: We observed the proliferation of resistant cells in (H1975R+) and out (H1975R-) of apitolisib treatment, cell cycle pattern, energy phenotyping/reprogramming, and the effects of combining Apitolisib with Vorinostat on the acquired proliferation of H1975R- cells. Results: The Proliferation of H1975R- cells increased, while that of H1975R+ cells remained suppressed. Both conditions showed a 5x decrease in the number of cells at the Go/G1 phase and doubled at S and G2/M phases (p< 0.0001). H1975R- cell survival was 80% compared with 20% in H975R+ cells treated with 7 μM vorinostat. Vorinostat effectively controlled acquired hyperproliferation of H1975R- cells. Conclusion: If a tumour becomes unresponsive to apitolisib, it is advisable to continue the inhibitor and consider a combination with non-tyrosine kinase inhibitors.