Therapeutic priority of the PI3K/AKT/mTOR pathway in small cell lung cancers as revealed by a comprehensive genomic analysis

Abstract

Introduction: The information regarding therapeutically relevant genomic alterations in small cell lung cancer (SCLC) is not well developed. We analyzed the SCLC genome using an integrative approach to stratify the targetable alterations.

Methods: We performed whole exon sequencing (n = 51) and copy number analysis (n =47) on surgically resected tumors and matched normal tissue samples from treatment-naive Japanese SCLC patients.

Results: The demographics of the 51 patients included in this study were as follows: median age, 67 years (range, 42-86 years); female, 9 (18%); history of smoking, 50 (98%); and pathological stage I/II/III/IV, 28/13/9/1, respectively. The average number of nonsynonymous mutations was 209 (range, 41-639; standard deviation, 130). We repeatedly confirmed the high prevalence of inactivating mutations in TP53 and RB1, and the amplification of MYC family members. In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 36% of the tumors: PIK3CA, 6%; PTEN, 4%; AKT2, 9%; AKT3, 4%; RICTOR, 9%; and mTOR, 4%. Furthermore, the individual changes in this pathway were mutually exclusive. Importantly, the SCLC cells harboring active PIK3CA mutations were potentially targetable with currently available PI3K inhibitors.

Conclusions: The PI3K/AKT/mTOR pathway is distinguishable in SCLC genomic alterations. Therefore, a sequencing-based comprehensive analysis could stratify SCLC patients by potential therapeutic targets.

FIGURE 1.

An overview of the key driver mutations and major associated clinical features of 47 SCLC samples. The number of events per gene is noted on the left. The genes are displayed as rows, and the samples are displayed as columns, with major associated clinical features. PY, pack years; MYC family*, MYC family altered samples.

FIGURE 2.

(A) The concentration–response cell survival curves of SCLC cell lines with or without genetic alteration in the PI3K/AKT/mTOR pathway in response to BEZ235 (nM) and Cisplatin (nM). The PIK3CA mutation positive cell line, H1048, is relatively sensitive to BEZ235. The H82 and H209 cell lines are negative controls. (B) Western blotting was used to investigate the impact of BEZ235 on AKT phosphorylation and S6RP phosphorylation in the SCLC cells. AKT was activated in H446 and H1048 cells, and it was inhibited after being treated with 10 nM BEZ235. AKT was amplified but not constitutively phosphorylated in the H1694 cells. AKT phosphorylation was not detected in the negative control cell lines, H82 and H209. With regard to factors located downstream of mTOR, S6RP was phosphorylated in all five SCLC cell lines. Especially, the phosphorylation level was high in AKT-activated H446 and H1048 cells. BEZ235 significantly reduced the phosphorylation of S6RP in all the cells.