PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer

Xuefeng Li; Cheng Li; Chenchen Guo; Qiqi Zhao; Jiayu Cao; Hsin-Yi Huang; Meiting Yue; Yun Xue; Yujuan Jin; Liang Hu; Hongbin Ji

doi:10.1016/j.jgg.2021.04.001

Volume 48 Issue 7

Jul. 2021

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Article Navigation > Journal of Genetics and Genomics > 2021 > 48(7): 640-651

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PI3K/Akt/mTOR signaling orchestrates the phenotypic transition and chemo-resistance of small cell lung cancer

doi: 10.1016/j.jgg.2021.04.001

Xuefeng Li^a,b,c,
Cheng Li^c,
Chenchen Guo^a,b,
Qiqi Zhao^a,b,d,
Jiayu Cao^b,e,
Hsin-Yi Huang^a,
Meiting Yue^a,b,
Yun Xue^a,b,
Yujuan Jin^a,
Liang Hu^a,
Hongbin Ji^a,b,d,f

a State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China;
b University of Chinese Academy of Sciences, Beijing 100049, China;
c Department of Medical Oncology, The First Affiliated Hospita, Hengyang MedicalSchool, University of South China, Hengyang, Hunan 421001, China;
d School of Life Science and Technology, Shanghai Tech University, Shanghai 200120, China;
e CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
f School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China

Funds:

This work was supported by the National Natural Science Foundation of China (82030083 to H.J., 81871875 to L.H.), the National Basic Research Program of China (2017YFA0505501 to H.J.

2020YFA0803300 to H.J.), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19020201 to H.J.), the National Natural Science Foundation of China (81872312 to H.J., 82011540007 to H.J., 31621003 to H.J., 81402371 to Y.J., 81802279 to H.H., 81902326 to X.W., 81602443 to X.L.), the Basic Frontier Scientific Research Program of Chinese Academy of Science (ZDBSLY-SM006 to H.J.), the International Cooperation Project of Chinese Academy of Sciences (153D31KYSB20190035 to H.J.), the Youth Innovation Promotion Association CAS (Y919S31371 to X.W.), the Natural Science Foundation of Hunan Province, China (2019JJ50550 to X.L.), Clinical Medical Technology Innovation Guide Project of Hunan (2020SK51827 to X.L.), Project of Scientific Research Plan of Hunan Provincial Health Commission (202103100127 to X.L.).

Received Date: 2021-01-28
Accepted Date: 2021-04-02
Rev Recd Date: 2021-04-02
Publish Date: 2021-07-20

Abstract

Abstract

Small cell lung cancer (SCLC) is a phenotypically heterogeneous disease with an extremely poor prognosis, which is mainly attributed to the rapid development of resistance to chemotherapy. However, the relation between the growth phenotypes and chemo-resistance of SCLC remains largely unclear. Through comprehensive bioinformatic analyses, we found that the heterogeneity of SCLC phenotype was significantly associated with different sensitivity to chemotherapy. Adherent or semiadherent SCLC cells were enriched with activation of the PI3K/Akt/mTOR pathway and were highly chemoresistant. Mechanistically, activation of the PI3K/Akt/mTOR pathway promotes the phenotypic transition from suspension to adhesion growth pattern and confers SCLC cells with chemo-resistance. Such chemo-resistance could be largely overcome by combining chemotherapy with PI3K/Akt/mTOR pathway inhibitors. Our findings support that the PI3K/Akt/mTOR pathway plays an important role in SCLC phenotype transition and chemo-resistance, which holds important clinical implications for improving SCLC treatment.
- SCLC,
- Heterogeneity,
- Growth pattern,
- Phenotype transition,
- Drug resistance,
- PI3K/Akt/mTOR pathway

These authors contributed equally to this article.

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References(52)

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