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

Hideki Makinoshima,Hiroki Nakanishi,Masahiro Tsuboi,Koichi Goto,Hibiki Udagawa,Ami Maruyama,Katsuya Tsuchihara,Shingo Matsumoto,Shigeki Umemura,Atsushi Ochiai,Sachiyo Mimaki,Hiroyasu Esumi,Genichiro Ishii,Seiji Niho,Takehiko Sasaki,Ayako Suzuki

doi:10.1158/0008-5472.can-17-2109

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 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 metabolomics as a tool for finding novel therapeutic biomarkers. Cancer Res; 78(9); 2179-90. ©2018 AACR.

Highlights

Small-cell lung cancer (SCLC) accounts for approximately 14% of all lung cancers
To investigate the efficacy of a PI3K/AKT/mTOR pathway inhibitor against SCLC, we investigated whether alterations in this pathway enhanced the sensitivity of SCLC cell lines to the PI3K/mTOR dual inhibitor gedatolisib
We found that SCLC cell lines could be categorized into two groups according to their susceptibility to gedatolisib treatment: four of the cell lines (H1048, DMS114, H187, and H446) were sensitive, with an IC50 value after 72 hours of treatment of

Summary

Introduction

Small-cell lung cancer (SCLC) accounts for approximately 14% of all lung cancers. It is an exceptionally aggressive neuroendocrine tumor with a high proliferative index and a strong predilection for early metastasis [1, 2]. The PI3K/AKT/mTOR signaling pathway plays a key role in cell proliferation, growth, survival, and protein synthesis [10,11,12,13]. It provides strong growth and survival signals to tumor cells and has profound effects on glucose and amino acid metabolism [13,14,15,16,17]. Class 1 PI3Ks play a key role in the biology of human cancer. Pharmacokinetic, and safety profiles are favorable, and it has advanced to phase I clinical evaluation [23], and the agent afforded acceptable tolerability and activity in patients with recurrent endometrial cancer in a phase II study [24]

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