Dabrafenib; Preclinical Characterization, Increased Efficacy when Combined with Trametinib, while BRAF/MEK Tool Combination Reduced Skin Lesions

Abstract

Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.

A Novel RAF Kinase Inhibitor with DFG-Out–Binding Mode: High Efficacy in BRAF-Mutant Tumor Xenograft Models in the Absence of Normal Tissue Hyperproliferation

“…Whereas some compounds, even though reasonably potent and selective BRAF inhibitors in in vitro experiments and efficacious in tumor xenograft models, induced hyperproliferation of various stratified and transitional epithelia in mice, in accordance with previous reports (8)(9)(10), others achieved similar efficacy in the absence of detectable histologic changes. Although some of these differences may be due to offtarget effects, we reasoned that different modes of drug-target interaction may play a fundamental role in determining the therapeutic index and thus the extent and duration of tumor responses.…”

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma

“…Owing to the modest improvement in PFS with BRAF‐ and MEK‐inhibitor monotherapies, development of resistance to BRAF inhibition, poor outcome in patients with BRAF ‐mutant melanoma after development of resistance to BRAF‐inhibitor monotherapy, and the associated severe cutaneous toxicity, there was an interest in combining oncogenic BRAF inhibition with downstream MEK inhibition in the MAPK pathway to help in improving the patient outcomes. A synergistic effect of the combination of dabrafenib and trametinib, via concomitant inhibition of the ERK, was observed in BRAF V600‐mutant melanoma cell lines, and delayed emergence of resistance was observed in BRAF V600‐mutant melanoma xenografts in vivo along with a decrease in skin toxicities compared with monotherapy 16. In a phase 2 study, the dabrafenib and trametinib combination significantly improved PFS and decreased the frequency of known BRAF inhibitor‐induced hyperproliferative skin lesions such as cutaneous squamous cell carcinoma, papilloma and hyperkeratosis, compared with dabrafenib monotherapy in patients with BRAF inhibitor‐naïve metastatic melanoma 17…”

Rational Approaches for Combination Therapy Strategies Targeting the MAP Kinase Pathway in Solid Tumors

“…In a preclinical mouse model, combination of BRAF and MEK inhibitors demonstrated enhanced inhibition of tumor xenograft growth as well as reduction in paradoxical activation of the MAPK pathway in BRAF-WT cells (41). The phase I/II study BRF113220 (NCT01072175) was the first to evaluate dabrafenib plus trametinib in patients with BRAF V600-mutant melanoma (42).…”