RESUMO
Lung cancer is the leading cause of cancer deaths worldwide, with non-small cell lung cancer (NSCLC) accounting for 80% of all lung cancers. Kirsten rat sarcoma viral oncogene homolog (KRAS) is one of the deadliest cancer-related proteins and plays a pivotal role in the most aggressive and lethal human cancers, including lung adenocarcinoma where it represents one of the most frequently mutated oncogene. Although therapeutic progresses have made an impact over the last decade, median survival for patients with advanced lung cancer remains disappointing, with a 5-year worldwide survival rate of <15%. For more than 20 years it has been recognized that constitutively active signaling downstream of KRAS is a fundamental driver of lung tumorigenesis. However, years of pursuit have failed to yield a drug that can safely curb KRAS activity; up to now no approved therapies exist for KRAS-mutant NSCLC. The aim of this review is to discuss the current knowledge of KRAS-mutated NSCLC, touching upon KRAS clinical relevance as a prognostic and predictive biomarker, with an emphasis on novel therapeutic approaches for the treatment of KRAS-variant NSCLC.
Assuntos
Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma de Pulmão , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Mutação , PrognósticoRESUMO
Selumetinib is a potent and selective inhibitor of MEK1 and 2 that is currently being clinically developed for the treatment of several human malignancies. Initially administered as free-base suspension, a more convenient Hyd-sulfate capsule formulation has recently been developed. Phase I studies revealed that acneiform dermatitis was the dose-limiting toxicity of both the free-base and capsule formulation given two-times a day at the maximum tolerated doses of 100 and 75 mg, respectively, with the capsule formulation resulting into a significantly higher drug bioavailability. Importantly, as a MEK inhibitor, selumetinib could be particularly effective in tumors with a hyperactivated Ras/Raf/MEK/ERK pathway, which might be the case of KRAS-mutant non-small-cell lung cancers (NSCLCs). Accordingly, a recent randomized Phase II study evaluating docetaxel plus selumetinib or placebo in KRAS-mutant pretreated advanced NSCLC patients has demonstrated a significant improvement in terms of response rate, progression-free survival and patient-reported outcomes in favor of the combination arm. These positive results support further clinical evaluation of selumetinib in NSCLC, and confirmatory ongoing and future trials will assess its role according to KRAS-mutation status and in combination regimens with other targeted agents.
Assuntos
Benzimidazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Genes ras , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Benzimidazóis/efeitos adversos , Benzimidazóis/química , Benzimidazóis/farmacologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: This retrospective study was undertaken to investigate the impact of specific mutant KRAS on clinical outcome to either gefitinib or erlotinib (EGFR tyrosine kinase inhibitor, EGFR-TKI) in patients with EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC). METHODS: Patients with an EGFR WT genotype who were treated with an EGFR-TKI for advanced disease at our Institution were identified. Simultaneous availability of KRAS mutation status was required for study inclusion. RESULTS: Sixty-seven patients were eligible. Median age was 60 years (39-84), and 10 patients (14.9%) had received an EGFR-TKI as upfront therapy. Overall, the median progression-free survival (PFS) and overall survival (OS) were 2.9 months and 18.0 months, respectively. KRAS mutant patients (n=18) experienced a significantly shorter PFS compared with those carrying a KRAS WT genotype (n=49) (1.6 months vs 3.0 months, respectively, P=0.04; HR=1.92). However, within the KRAS mutant group a great variability in terms of sensitivity to treatment was noted (PFS ranging from 0.7 months to 38.7 months). KRAS codon 13 mutant patients (n=4) experienced the worse outcome when compared with KRAS codon 12 mutants (n=14) and KRAS WT patients (P<0.0001 and P=0.01 for PFS and OS, respectively). CONCLUSIONS: Though we found that EGFR WT/KRAS mutant advanced NSCLC patients are associated with an increased resistance to treatment, specific mutant KRAS may account for differential sensitivity to an EGFR-TKI. KRAS codon 13 mutants are those who seem to experience the worse clinical outcome.