Journal
CANCER RESEARCH
Volume 78, Issue 9, Pages 2179-2190Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-2109
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Funding
- Ministry of Education, Culture, Sports, Science and Technology, Japan
- Ministry of Health, Labour and Welfare, Japan
- Japan Agency for Medical Research and Development (AMED)
- National Cancer Center Research and Development Fund [28-A-9]
- Yamagata Prefecture and Tsuruoka City
- Grants-in-Aid for Scientific Research [17K07189, 16K14619] Funding Source: KAKEN
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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 is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment. Significance: These findings identify features that determine sensitivity of SCLC to PI3K pathway inhibition and support meta-bolomics as a tool for finding novel therapeutic biomarkers. (C) 2018 AACR.
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