RESUMO
PURPOSE: Approximately, 45-65% stage I non-small cell lung cancer (NSCLC) patients with surgical resection relapse within 5 years. Therefore, it is urgent to identify the predictors involved in the relapse of stage I NSCLC. METHODS/PATIENTS: Targeted sequencing was used to examine the mutation of tumor tissues and matched adjacent normal tissues from 35 patients with stage I lung adenocarcinoma (LUAD). Then, tissue microarrays containing tumor tissues from 149 stage I LUAD patients were used to assess protein expression of frequently mutated genes by immunohistochemistry. COX regression model was used to evaluate the impacts of frequently mutated genes and their protein expression on relapse-free survival (RFS) in stage I LUAD. RESULTS AND CONCLUSIONS: Three hundred and twenty-nine non-synonymous somatic variants were identified in 161 genes among these 35 patients. EGFR, TP53, LRP1B, RBM10, KRAS, NTRK3, RB1, ALK, APC, FAT2, KEAP1, MED12 and MLL3 were described as frequently mutated genes with prevalence more than 10%. Patients harboring KRAS mutation had more relapse in 1 year after surgical resection. For the expression of these frequently mutated genes in 149 stage I patients, multivariate Cox regression analyses showed that the expression of RBM10 was positively associated with RFS in all patients (HR 0.40, 95% CI 0.15-1.0, p = 0.052), and the expression of APC was negative associated with RFS in patients with EGFR mutations (HR 3.10, 95% CI 1.54-6.26, p = 0.002). Stage I LUAD patients with KRAS mutation or low RBM10 expression are inclined to receive more positive intervention rather than just disease surveillance.
Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/cirurgia , Proteína 1 Associada a ECH Semelhante a Kelch , Proteínas Proto-Oncogênicas p21(ras)/genética , Recidiva Local de Neoplasia/genética , Fator 2 Relacionado a NF-E2 , Adenocarcinoma de Pulmão/genética , Mutação , Receptores ErbB/genética , Proteínas de Ligação a RNA/genéticaRESUMO
AT-101 is a BH3 mimetic and pan-Bcl-2 inhibitor that has shown potent anticancer activity in non-small-cell lung cancer (NSCLC) in murine models, but failed to show clinical efficacy when used in combination with docetaxel in NSCLC patients. Our recent study has demonstrated that AT-101 enhanced the antitumor effect of cisplatin (CDDP) in a murine model of NSCLC via inhibition of the interleukin-6/signal transducer and activator of transcription 3 (STAT3) pathway. This study explored the underlying mechanisms for the enhanced anticancer activity of CDDP by AT-101. Our results show that, when compared with monotherapy, AT-101 significantly enhanced the inhibitory effects of CDDP on proliferation and migration of A549 cells and on tube formation and migration in human umbilical vein endothelial cells. AT-101 promoted the proapoptotic activity of CDDP in A549 cells. AT-101 also enhanced the inhibitory effect of CDDP on DNA repair and redox activities of apurinic/apyrimidinic endonuclease 1 (APE1) in A549 cells. In tumor tissues from nude mice treated with AT-101 plus CDDP or monotherapy, the combination therapy resulted in greater inhibition of angiogenesis and tumor cell proliferation than the monotherapy. These results suggest that AT-101 can enhance the antitumor activity of CDDP in NSCLC via inhibition of APE1 DNA repair and redox activities and by angiogenesis and induction of apoptosis, but other mechanisms cannot be excluded. We are now conducting a Phase II trial to examine the clinical efficacy and safety profile of combined use of AT-101 plus CDDP in advanced NSCLC patients.