Activation of PI3K/AKT Pathway Is a Potential Mechanism of Treatment Resistance in Small Cell Lung Cancer

Ying Jin, Yamei Chen, Huarong Tang, Xiao Hu, Shawna M. Hubert, Qian Li, Dan Su, Haimiao Xu, Yun Fan, Xinmin Yu, Qixun Chen, Jinshi Liu, Wei Hong, Yujin Xu, Huan Deng, Dapeng Zhu, Pansong Li, Yuhua Gong, Xuefeng Xia, Carl M. GayJianjun Zhang, Ming Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Here, we have investigated treatment resistance mechanisms in small cell lung cancer (SCLC) by focusing on comparing the genotype and phenotype in tumor samples of treatment-resistant and treatment-sensitive SCLC. Experimental Design: We conducted whole-exome sequencing on paired tumor samples at diagnosis and relapse from 11 patients with limited-stage (LS)-SCLC and targeted sequencing of 1,021 cancer-related genes on cell-free DNA at baseline and paired relapsed samples from 9 additional patients with LS-SCLC. Furthermore, we performed label-free mass spectrometry-based proteomics on tumor samples from 28 chemo-resistant and 23 chemo-sensitive patients with extensive-stage (ES)-SCLC. The main findings were validated in vitro in chemo-sensitive versus chemo-resistant SCLC cell lines and analyses of transcriptomic data of SCLC cell lines from a public database. Results: Genomic analyses demonstrated that at relapse of LSSCLC, genes in the PI3K/AKT signaling pathway were enriched for acquired somatic mutations or high-frequency acquired copynumber variants. Pathway analysis on differentially upregulated proteins from ES-SCLC cohort revealed enrichment in theHIF-1 signaling pathway. Importantly, 7 of 62 PI3K/AKT pathway genes containing acquired somatic copy-number amplifications were enriched in HIF-1 pathway. Analyses of transcriptomic data of SCLC cell lines from public databases confirmed upregulation of PI3K/AKT and HIF-1 pathways in chemo-resistant SCLC cell lines. Furthermore, chemotherapyresistant cell lines could be sensitive to PI3K inhibitors in vitro. Conclusions: PI3K/AKT pathway activation may be one potential mechanism underlying therapeutic resistance of SCLC. This finding warrants further investigation and provides a possible approach to reverse resistance to chemo/radiotherapy.

Original languageEnglish (US)
Pages (from-to)526-539
Number of pages14
JournalClinical Cancer Research
Volume28
Issue number3
DOIs
StatePublished - Feb 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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