Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models

Autor: Samuel Waxman, Ethan Dmitrovsky, James R. Rigas, Tian Ma, Cherie P. Erkmen, Gregory J. Tsongalis, William C. Nugent, Vincent A. Memoli, Jobin Cyrus, Alexander M. Busch, Marc Seltzer, Sarah J. Freemantle, Xi Liu, David W. Johnstone, Jonathan M. Kurie, Fabrizio Galimberti, Konstantin H. Dragnev
Rok vydání: 2011
Předmět:
Male
Cancer Research
Lung Neoplasms
medicine.disease_cause
Tyrosine-kinase inhibitor
Immunoenzyme Techniques
Mice
Carcinoma
Non-Small-Cell Lung
Antineoplastic Combined Chemotherapy Protocols
Tumor Cells
Cultured
Cyclin D1
Epidermal growth factor receptor
Erlotinib Hydrochloride
Bexarotene
Middle Aged
ErbB Receptors
Survival Rate
Treatment Outcome
Oncology
Female
Erlotinib
KRAS
medicine.drug
Tetrahydronaphthalenes
medicine.drug_class
Immunoblotting
Mice
Transgenic
Biology
Proto-Oncogene Proteins p21(ras)
Necrosis
Proto-Oncogene Proteins
medicine
Biomarkers
Tumor
Animals
Humans
Lung cancer
Survival rate
Aged
Salvage Therapy
Mouth Mucosa
medicine.disease
respiratory tract diseases
Drug Resistance
Neoplasm
Mutation
Cancer research
biology.protein
Quinazolines
ras Proteins
Neoplasm Recurrence
Local
Zdroj: Cancer prevention research (Philadelphia, Pa.). 4(6)
ISSN: 1940-6215
Popis: The rexinoid bexarotene represses cyclin D1 by causing its proteasomal degradation. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib represses cyclin D1 via different mechanisms. We conducted a preclinical study and 2 clinical/translational trials (a window-of-opportunity and phase II) of bexarotene plus erlotinib. The combination repressed growth and cyclin D1 expression in cyclin-E- and KRAS/p53-driven transgenic lung cancer cells. The window-of-opportunity trial in early-stage non–small-cell lung cancer (NSCLC) patients (10 evaluable), including cases with KRAS mutations, repressed cyclin D1 (in tumor biopsies and buccal swabs) and induced necrosis and inflammatory responses. The phase II trial in heavily pretreated, advanced NSCLC patients (40 evaluable; a median of two prior relapses per patient (range, 0–5); 21% with prior EGFR-inhibitor therapy) produced three major clinical responses in patients with prolonged progression-free survival (583-, 665-, and 1,460-plus days). Median overall survival was 22 weeks. Hypertriglyceridemia was associated with an increased median overall survival (P = 0.001). Early PET (positron emission tomographic) response did not reliably predict clinical response. The combination was generally well tolerated, with toxicities similar to those of the single agents. In conclusion, bexarotene plus erlotinib was active in KRAS-driven lung cancer cells, was biologically active in early-stage mutant KRAS NSCLC, and was clinically active in advanced, chemotherapy-refractory mutant KRAS tumors in this study and previous trials. Additional lung cancer therapy or prevention trials with this oral regimen are warranted. Cancer Prev Res; 4(6); 818–28. ©2011 AACR.
Databáze: OpenAIRE
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