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

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.

• Authors: Konstantin H Dragnev, Tian Ma, Jobin Cyrus, Fabrizio Galimberti, Vincent Memoli, Alexander M Busch, Gregory J Tsongalis, Marc Seltzer, David Johnstone, Cherie P Erkmen, William Nugent, James R Rigas, Xi Liu, Sarah J Freemantle, Jonathan M Kurie, Samuel Waxman, Ethan Dmitrovsky
• Journal: Cancer prevention research (Philadelphia, Pa.) (Cancer Prev Res (Phila)) Vol. 4 Issue 6 Pg. 818-28 (Jun 2011) ISSN: 1940-6215 [Electronic] United States
• PMID: 21636548 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• CCND1 protein, human
• KRAS protein, human
• Proto-Oncogene Proteins
• Quinazolines
• Tetrahydronaphthalenes
• Cyclin D1
• Bexarotene
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Aged
• Animals
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bexarotene
• Biomarkers, Tumor (genetics)
• Carcinoma, Non-Small-Cell Lung (genetics, pathology, prevention & control)
• Cyclin D1 (metabolism)
• Drug Resistance, Neoplasm (drug effects)
• ErbB Receptors (genetics)
• Erlotinib Hydrochloride
• Female
• Humans
• Immunoblotting
• Immunoenzyme Techniques
• Lung Neoplasms (genetics, pathology, prevention & control)
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Mouth Mucosa (cytology, drug effects, metabolism)
• Mutation (genetics)
• Necrosis
• Neoplasm Recurrence, Local (genetics, pathology, prevention & control)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Quinazolines (administration & dosage)
• Salvage Therapy
• Survival Rate
• Tetrahydronaphthalenes (administration & dosage)
• Treatment Outcome
• Tumor Cells, Cultured
• ras Proteins (genetics)