RESUMO
Further characterization of thymic epithelial tumors (TETs) is needed. Genomic information from 102 evaluable TETs from The Cancer Genome Atlas (TCGA) dataset and from the IU-TAB-1 cell line (type AB thymoma) underwent clustering analysis to identify molecular subtypes of TETs. Six novel molecular subtypes (TH1-TH6) of TETs from the TCGA were identified, and there was no association with WHO histologic subtype. The IU-TAB-1 cell line clustered into the TH4 molecular subtype and in vitro testing of candidate therapeutics was performed. The IU-TAB-1 cell line was noted to be resistant to everolimus (mTORC1 inhibitor) and sensitive to nelfinavir (AKT1 inhibitor) across the endpoints measured. Sensitivity to nelfinavir was due to the IU-TAB-1 cell line's gain-of function (GOF) mutation in PIK3CA and amplification of genes observed from array comparative genomic hybridization (aCGH), including AURKA, ERBB2, KIT, PDGFRA and PDGFB, that are known upregulate AKT, while resistance to everolimus was primarily driven by upregulation of downstream signaling of KIT, PDGFRA and PDGFB in the presence of mTORC1 inhibition. We present a novel molecular classification of TETs independent of WHO histologic subtype, which may be used for preclinical validation studies of potential candidate therapeutics of interest for this rare disease.
RESUMO
PURPOSE: KRAS-mutated (KRASMUT) non-small-cell lung cancer (NSCLC) is emerging as a heterogeneous disease defined by comutations, which may confer differential benefit to PD-(L)1 immunotherapy. In this study, we leveraged computational biological modeling (CBM) of tumor genomic data to identify PD-(L)1 immunotherapy sensitivity among KRASMUT NSCLC molecular subgroups. MATERIALS AND METHODS: In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients with KRASMUT NSCLC. These genomic data were input into the CBM, in which customized protein networks were characterized for each tumor. The CBM evaluated sensitivity to PD-(L)1 immunotherapy using three metrics: programmed death-ligand 1 expression, dendritic cell infiltration index (nine chemokine markers), and immunosuppressive biomarker expression index (14 markers). RESULTS: Genotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics: KRASMUT/TP53MUT, KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, KRASMUT/KEAP1MUT, KRASMUT/STK11MUT/KEAP1MUT, KRASMUT/PIK3CAMUT, KRAS MUT/ATMMUT, and KRASMUT without comutation. CBM identified PD-(L)1 immunotherapy sensitivity in the KRASMUT/TP53MUT, KRASMUT/PIK3CAMUT, and KRASMUT alone subgroups and resistance in the KEAP1MUT containing subgroups. There was insufficient genomic information to elucidate PD-(L)1 immunotherapy sensitivity by the CBM in the KRASMUT/CDKN2A/B/CMUT, KRASMUT/STK11MUT, and KRASMUT/ATMMUT subgroups. In an exploratory clinical cohort of 34 patients with advanced KRASMUT NSCLC treated with PD-(L)1 immunotherapy, the CBM-assessed overall survival correlated well with actual overall survival (r = 0.80, P < .001). CONCLUSION: CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of KRASMUT NSCLC, in line with previous literature. These data provide proof-of-concept that computational modeling of tumor genomics could be used to expand on hypotheses from clinical observations of patients receiving PD-(L)1 immunotherapy and suggest mechanisms that underlie PD-(L)1 immunotherapy sensitivity.