Therapeutic Priority of the PI3K/AKT/mTOR Pathway in Small Cell Lung Cancers as Revealed by a Comprehensive Genomic Analysis Shigeki Umemura, MD, PhD,

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Therapeutic Priority of the PI3K/AKT/mTOR Pathway in Small Cell Lung Cancers as Revealed by a Comprehensive Genomic Analysis Shigeki Umemura, MD, PhD, Sachiyo Mimaki, MS, Hideki Makinoshima, PhD, Satoshi Tada, MS, Genichiro Ishii, MD, PhD, Hironobu Ohmatsu, MD, Seiji Niho, MD, PhD, Kiyotaka Yoh, MD, Shingo Matsumoto, MD, PhD, Akiko Takahashi, MD, Masahiro Morise, MD, PhD, Yuka Nakamura, BS, Atsushi Ochiai, MD, PhD, Kanji Nagai, MD, PhD, Reika Iwakawa, PhD, Takashi Kohno, PhD, Jun Yokota, MD, PhD, Yuichiro Ohe, MD, PhD, Hiroyasu Esumi, MD, PhD, Katsuya Tsuchihara, MD, PhD, Koichi Goto, MD, PhD Journal of Thoracic Oncology Volume 9, Issue 9, Pages 1324-1331 (September 2014) DOI: 10.1097/JTO.0000000000000250 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

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. Journal of Thoracic Oncology 2014 9, 1324-1331DOI: (10.1097/JTO.0000000000000250) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

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. Journal of Thoracic Oncology 2014 9, 1324-1331DOI: (10.1097/JTO.0000000000000250) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions