PI3K-AKT pathway alterations are revealed as a potential mechanism of chemoradiation resistance in small cell lung cancer by whole-exome sequencing.

Abstract

e20573 Background: Although small-cell lung cancer (SCLC) is sensitive to chemotherapy and radiotherapy initially, nearly all patients recur often with treatment-resistant disease. Comparing genomic profiles and clonal architecture of paired treatment-naïve and recurrent tumors may provide novel insights into mechanisms underlying recurrence and susceptibility to further treatment. Methods: Paired tumor samples procured at diagnosis and relapse were collected from 11 patients (pts) with limited-stage SCLC treated with concurrent chemoradiation (CCRT). All tissues underwent whole exome sequencing (WES). Genomic landscape including somatic mutations, somatic copy number alterations (SCNAs), and clonal architecture were compared between treatment-naïve and paired recurrent tumor samples. Baseline and paired recurrent plasma samples from another 9 pts with SCLC treated with CCRT were performed deep sequencing using a targeted panel containing 1021 cancer related genes. Results: We observed TP53 and RB1 alterations including mutations and SCNAs in the majority of treatment-naïve ( TP53 in 10 of 11, RB1 in 7 of 11 pts) and relapse samples ( TP53 in 8 of 11, RB1 in 8 of 11 pts). Tobacco exposure related mutational signature was most or second predominant in 11 pre-treatment and 9 recurrent samples, respectively. Compared with primary tumors, relapsed tumors showed significantly increased number of mutations (220 vs 210, p = 0.016). A high proportion of shared mutations between baseline and PD samples ranging from 39% to 94% was observed. More than half (n = 6) of the 11 pts had increased chromosomal instability in recurrent tumors. A total of 687 relapse-specific also called acquired mutations in 633 genes were identified, in which 158 mutations with cancer cell fraction (CCF) > 0.6. These genes were enriched in PI3K-ATK signaling pathway and covered 73% (8/11) pts. Of the 9 paired plasma samples performed by targeted sequencing, genes with specific mutations and mutations with increased CCF in relapsed plasma samples were also enriched in PI3K-ATK pathway. In vitro proliferation assay indicated that PI3K inhibitor gave rise to a marked decrease in proliferation after combined with cisplatin, implying the potential mechanism of chemoradiation resistance. The number of clones in recurrent samples was higher than that in pre-treatment samples (13 vs 12, p = 0.004), indicating that new clones emerged under the treatment and tumor heterogeneity increased. Patients characterized by weakening of the major treatment-naïve clone tended to exhibit relatively longer PFS than those with sustaining major clone in both b baseline and relapsed tumors (p = 0.034). Conclusions: PI3K-ATK pathway alterations are frequent in recurrent SCLCs, which may be a candidate resistant mechanism after chemoradiation. PFS is probably associated with clonal evolutionary pattern.