RESUMO
While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.
Assuntos
Adenocarcinoma/genética , Adenocarcinoma/imunologia , Genes ras , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Quinases Proteína-Quinases Ativadas por AMP , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão , Proliferação de Células/genética , Feminino , Expressão Gênica , Humanos , Vigilância Imunológica/genética , Neoplasias Pulmonares/patologia , Masculino , Proteínas Serina-Treonina Quinases/imunologia , Proteínas Proto-Oncogênicas p21(ras)/biossíntese , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Transdução de Sinais , Proteína Supressora de Tumor p53/imunologiaRESUMO
Serine/threonine kinase IKBKE is a newly identified oncogene; however, its regulation remains elusive. Here, we provide evidence that IKBKE is a downstream target of signal transducer and activator of transcription 3 (STAT3) and that tobacco components induce IKBKE expression through STAT3. Ectopic expression of constitutively active STAT3 increased IKBKE mRNA and protein levels, whereas inhibition of STAT3 reduced IKBKE expression. Furthermore, expression levels of IKBKE are significantly associated with STAT3 activation and tobacco use history in non-small cell lung cancer (NSCLC) patients examined. In addition, we show induction of IKBKE by two components of cigarette smoke, nicotine and nicotine-derived nitrosamine ketone (NNK). Upon exposure to nicotine or NNK, cells express high levels of IKBKE protein and mRNA, which are largely abrogated by inhibition of STAT3. Characterization of the IKBKE promoter revealed two STAT3-response elements. The IKBKE promoter directly bound to STAT3 and responded to nicotine and NNK stimulation. Notably, enforcing expression of IKBKE induces chemoresistance, whereas knockdown of IKBKE not only sensitizes NSCLC cells to chemotherapy but also abrogates STAT3- and nicotine-induced cell survival. These data indicate for the first time that IKBKE is a direct target of STAT3 and is induced by tobacco carcinogens through STAT3 pathway. In addition, our study also suggests that IKBKE is an important therapeutic target and could have a pivotal role in tobacco-associated lung carcinogenesis.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Quinase I-kappa B/metabolismo , Fator de Transcrição STAT3/metabolismo , Fumar , Carcinoma Pulmonar de Células não Pequenas/genética , Proliferação de Células , Sobrevivência Celular , Humanos , Quinase I-kappa B/genética , Cetonas/farmacologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Nicotina/farmacologia , Nitrosaminas/farmacologia , Regiões Promotoras Genéticas , Interferência de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Transdução de Sinais , NicotianaRESUMO
BACKGROUND: Lung cancer continues to be the leading cause of cancer-related deaths for Americans. As most patients present with nonsurgically curable disease, major efforts have been made in the treatment of advanced non-small-cell lung cancer (NSCLC) with chemotherapy. Several new agents and new combinations of chemotherapy are available. METHODS: The author reviews randomized clinical trials investigating chemotherapy for advanced NSCLC in chemotherapy-naive patients, in patients who present with relapsed or progressive disease, and in elderly patients. Therapies that incorporate new biological agents to target specific aberrations in lung cancer are discussed. RESULTS: Several clinical trials demonstrate improvement in overall survival as well as quality of life with chemotherapy treatment of advanced NSCLC. Better options are available for patients who have relapsed after first-line chemotherapy, and treatment of elderly patients with chemotherapy has demonstrated benefit in survival and quality of life. New agents that target molecular pathways are being tested in patients with early-stage disease. CONCLUSIONS: Despite progress with newer agents for the treatment of advanced NSCLC, only 14% of patients with the disease are alive at 5 years after initial diagnosis. New therapies are needed.
