Metabolic Determinants of Sensitivity to Phosphatidylinositol 3-Kinase Pathway Inhibitor in Small-Cell Lung Carcinoma

Cancer Research
Hideki MakinoshimaKatsuya Tsuchihara

Abstract

Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here, we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1, a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors...Continue Reading

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Citations

Dec 11, 2019·Cells·Cedric MagawayEstela Jacinto
Jul 7, 2019·Journal of Hematology & Oncology·Hui HuaYangfu Jiang
Feb 21, 2019·Molecular Cancer·Jing YangXiawei Wei
Feb 18, 2021·Metabolomics : Official Journal of the Metabolomic Society·Yuichiro NishidaKeitaro Tanaka
Apr 4, 2021·International Journal of Molecular Sciences·Rosalin MishraJoan T Garrett

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