Faculty Collaboration Database

Bexarotene plus erlotinib suppress lung carcinogenesis independent of KRAS mutations in two clinical trials and transgenic models. Cancer Prev Res (Phila) 2011 Jun;4(6):818-28

Date

06/04/2011

Pubmed ID

21636548

Pubmed Central ID

PMC3108499

DOI

10.1158/1940-6207.CAPR-10-0376

Scopus ID

2-s2.0-79957860099 (requires institutional sign-in at Scopus site)   52 Citations

Abstract

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.

Author List

Dragnev KH, Ma T, Cyrus J, Galimberti F, Memoli V, Busch AM, Tsongalis GJ, Seltzer M, Johnstone D, Erkmen CP, Nugent W, Rigas JR, Liu X, Freemantle SJ, Kurie JM, Waxman S, Dmitrovsky E

Author

David Johnstone MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Animals
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
Carcinoma, Non-Small-Cell Lung
Cyclin D1
Drug Resistance, Neoplasm
ErbB Receptors
Erlotinib Hydrochloride
Female
Humans
Immunoblotting
Immunoenzyme Techniques
Lung Neoplasms
Male
Mice
Mice, Transgenic
Middle Aged
Mouth Mucosa
Mutation
Necrosis
Neoplasm Recurrence, Local
Proto-Oncogene Proteins
Proto-Oncogene Proteins p21(ras)
Quinazolines
Salvage Therapy
Survival Rate
Tetrahydronaphthalenes
Treatment Outcome
Tumor Cells, Cultured
ras Proteins