@article{9df9f911c9e041baa3e21a8a89130f21,
title = "The Effect of LKB1 Activity on the Sensitivity to PI3K/mTOR Inhibition in Non–Small Cell Lung Cancer",
abstract = "Introduction: Liver kinase B1 (LKB1), also called serine/threonine kinase 11 (STK11), is a tumor suppressor that functions as master regulator of cell growth, metabolism, survival, and polarity. Approximately 30% to 35% of patients with NSCLC possess inactivated liver kinase B1 gene (LKB1), and these patients respond poorly to anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy. Therefore, novel therapies targeting NSCLC with LKB1 loss are needed. Methods: We used a new in silico signaling analysis method to identify the potential therapeutic targets and reposition drugs by integrating gene expression data with the Kyoto Encyclopedia of Genes and Genomes signaling pathways. LKB1 wild-type and LKB1-deficient NSCLC cell lines, including knockout clones generated by clustered regularly interspaced short pallindromic repeats–Cas9, were treated with inhibitors of mechanistic target of rapamycin kinase (mTOR) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and a dual inhibitor. Results: In silico experiments showed that inhibition of both mTOR and PI3K can be synergistically effective in LKB1-deficient NSCLC. In vitro and in vivo experiments showed the synergistic effect of mTOR inhibition and PI3K inhibition in LKB1-mutant NSCLC cell lines. The sensitivity to dual inhibition of mTOR and PI3K is higher in LKB1-mutant cell lines than in wild-type cell lines. A higher compensatory increase in Akt phosphorylation after rapamycin treatment of LKB1-deficient cells than after rapamycin treatment of LKB1 wild-type cells is responsible for the synergistic effect of mTOR and PI3K inhibition. Dual inhibition of mTOR and PI3K resulted in a greater decrease in protein expression of cell cycle–regulating proteins in LKB1 knockout cells than in LKB1 wild-type cells. Conclusion: Dual molecular targeted therapy for mTOR and PI3K may be a promising therapeutic strategy in the specific population of patients with lung cancer with LKB1 loss.",
keywords = "LKB1, Lung cancer, Molecular targeted agent, PI3K, mTOR",
author = "Takehito Shukuya and Tadaaki Yamada and Koenig, {Michael J.} and Jielin Xu and Tamio Okimoto and Fuhai Li and Amann, {Joseph M.} and Carbone, {David P.}",
note = "Funding Information: This study was supported by the DallePezze Thoracic Oncology Fund, a grant from the National Cancer Institute ( 5U10CA180950 [to Dr. Carbone]), and Shared Resource at The Ohio State University Comprehensive Cancer Center ( P30CA016058 ). This work was also supported by a Lilly Oncology Fellowship from The Japanese Respiratory Society, an alumni scholarship from Juntendo University School of Medicine, a research fellowship from Uehara Memorial Foundation, and a Pelotonia postdoctoral fellowship (to Dr. Shukuya). We appreciate the gift of the Calu-1, HCC15, H23, H157, H358, H520, H1299, and H2087 cells that were provided by John Minna and Luc Girard (University of Texas Southwestern, Dallas, TX). Funding Information: This study was supported by the DallePezze Thoracic Oncology Fund, a grant from the National Cancer Institute (5U10CA180950 [to Dr. Carbone]), and Shared Resource at The Ohio State University Comprehensive Cancer Center (P30CA016058). This work was also supported by a Lilly Oncology Fellowship from The Japanese Respiratory Society, an alumni scholarship from Juntendo University School of Medicine, a research fellowship from Uehara Memorial Foundation, and a Pelotonia postdoctoral fellowship (to Dr. Shukuya). We appreciate the gift of the Calu-1, HCC15, H23, H157, H358, H520, H1299, and H2087 cells that were provided by John Minna and Luc Girard (University of Texas Southwestern, Dallas, TX). Disclosure: Dr. Shukuya reports personal fees from Eli Lilly and Company, Nichi-Iko Pharmaceutical Co., and Sanofi outside the submitted work. Dr. Carbone reports personal fees from Abbvie, Adaptimmune, Agenus, Amgen, Ariad, AstraZeneca, Biocept, Boehringer Ingelheim, Celgene, Clovis, EMD Serono, Foundation Medicine, Genentech/Roche, Gritstone, Guardant Health, Helsinn, Humana, Incyte, Inivata, Inovio, Janssen, Kyowa Kirin, Merck, Merck Sharp Dohme, Novartis, Palobiofarma, Pfizer, prIME Oncology, Stemcentrx, Takeda, and Teva, as well as grants and personal fees from Bristol Myers-Squibb, outside the submitted work. The remaining authors declare no conflict of interest. Publisher Copyright: {\textcopyright} 2019 International Association for the Study of Lung Cancer",
year = "2019",
month = jun,
doi = "10.1016/j.jtho.2019.02.019",
language = "English (US)",
volume = "14",
pages = "1061--1076",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "6",
}