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Activation of PI3K/AKT pathway is revealed as a mechanism of chemoresistance 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.Gay  Jianjun Zhang  Ming Chen  
【摘要】: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 SCLC.Methods: 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 SCLC.Results: 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 HIF-1.Furthermore, in vitro-derived chemo-resistant SCLC cell lines demonstrate reversal of chemotherapy resistance upon PI3 K.Conclusions: 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.

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