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Activation of PI3K/AKT pathway is revealed as a mechanism of chemoresistance in small cell lung cancer

Activation of PI3K/AKT pathway is revealed as a mechanism of...

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2021年中国肿瘤标志物学术大会暨第十五届肿瘤标志物青年科学家论坛

作者： 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.Gay Jianjun Zhang Ming Chen The Cancer Hospital of the University of Chinese Academy of Sciences 中国科学院肿瘤与基础医学研究所浙江省放射肿瘤学重点实验室 Department of Thoracic/Head and Neck Medical Oncology the University of Texas MD Anderson Cancer Center Department of Genomic Medicine the University of Texas MD Anderson Cancer Center 中山大学肿瘤防治中心(中山大学附属肿瘤医院中山大学肿瘤研究所)

Purpose: There is an urgent need to elucidate mechanisms involved in chemoresistance in SCLC. Here we have investigated the mechanisms of chemoresistance in SCLC, focusing on comparing the genotype and phenotype in tumor samples of chemo-resistant and chemo-sensitive ***: We conducted whole-exome sequencing(WES) on paired tumor samples at diagnosis and relapse collected from 11 patients with SCLC treated with standard chemoradiation to investigate mechanisms of chemoresistance. Additionally, we performed targeted sequencing of 1,021 cancerrelated genes on cell free DNA(cfDNA) obtained at baseline from 9 additional patients and paired relapsed samples. Furthermore, we performed label-free mass spectrometry-(MS-) based proteomics on tumor samples derived from 28 chemo-resistant and 23 chemo-sensitive patients with ***: We found that numerous previously reported mutated genes were identified both in treatmentna?ve and post-treatment SCLCs in our cohort, while numerous relapse-specific mutations and copy number variants(CNVs) were also identified. At relapse, genes in the PI3 K/ATK signaling pathway were enriched for acquired somatic mutations or high frequency acquired CNVs. Pathway analysis found that genes with differentially upregulated expressed proteins were enriched in HIF-1 signaling pathway. Interestingly, 12 of 96 PI3 K/AKT pathway genes containing acquired somatic copy number amplification were enriched in HIF-1 pathway, and most of them were located upstream of ***, in vitro-derived chemo-resistant SCLC cell lines demonstrate reversal of chemotherapy resistance upon PI3 ***: Overall, our findings point to an important role for PI3 K/AKT pathway activation in SCLC chemoresistance. PI3 K/ATK pathway targeting could be a viable strategy to reverse chemoresistance.

关键词： small cell lung cancer whole-exome sequencing mechanism of chemoresistance PI3K/AKT pathway

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