Abstract
Clinical trials of selective RAF inhibitors in patients with melanoma tumors harboring activated BRAFV600E have produced very promising results, and a RAF inhibitor has been approved for treatment of advanced melanoma. However, about a third of patients developed resectable skin tumors during the course of trials. This is likely related to observations that RAF inhibitors activate extracellular signal-regulated kinase (ERK) signaling, stimulate proliferation, and induce epithelial hyperplasia in preclinical models. Because these findings raise safety concerns about RAF inhibitor development, we further investigated the underlying mechanisms. We showed that the RAF inhibitor PF-04880594 induces ERK phosphorylation and RAF dimerization in those epithelial tissues that undergo hyperplasia. Hyperplasia and ERK hyperphosphorylation are prevented by treatment with the mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitor PD-0325901 at exposures that extrapolate to clinically well-tolerated doses. To facilitate mechanistic and toxicologic studies, we developed a three-dimensional cell culture model of epithelial layering that recapitulated the RAF inhibitor-induced hyperplasia and reversal by MEK inhibitor in vitro. We also showed that PF-04880594 stimulates production of the inflammatory cytokine interleukin 8 in HL-60 cells, suggesting a possible mechanism for the skin flushing observed in dogs. The complete inhibition of hyperplasia by MEK inhibitor in epithelial tissues does not seem to reduce RAF inhibitor efficacy and, in fact, allows doubling of the PF-04880594 dose without toxicity usually associated with such doses. These findings indicated that combination treatment with MEK inhibitors might greatly increase the safety and therapeutic index of RAF inhibitors for the treatment of melanoma and other cancers.
Highlights
The BRAF protein kinase plays a central role in promoting normal cell proliferation and survival as a component of the RAS/RAF/mitogen-activated protein/extracellular signal–regulated kinase (MEK)/extracellular signal– regulated kinase (ERK) signaling pathway
On the basis of these observations, we investigated whether RAF inhibitor–induced hyperplasia was associated with ERK activation and BRAFCRAF dimerization in hyperplastic tissues and, most importantly, whether hyperplasia could be prevented by doses of MEK inhibitor that would extrapolate to clinically safe doses
It has been shown that a series of RAF inhibitors induce hyperplasia in multiple epithelial tissues and that hyperplasia in the nonglandular stomach epithelium can be prevented by coadministration of a MEK inhibitor, www.aacrjournals.org suggesting ERK activation as a contributing factor [8]
Summary
The BRAF protein kinase plays a central role in promoting normal cell proliferation and survival as a component of the RAS/RAF/MEK/ERK signaling pathway. The selective RAF inhibitor vemurafenib (PLX4032) was recently approved by the U.S Food and Drug Administration for treatment of metastatic melanomas in patients with BRAFV600E mutation. In a pivotal phase III trial of 675 patients with previously untreated metastatic melanoma, 74% had a reduction in risk of progression or death with vemurafenib compared with the reference drug, dacarbazine [4]. Mean progression-free survival with vemurafenib was 5.3 months, compared with 1.6 months for the dacarbazine cohort, and response rates of 48% with vemurafenib and 5% with dacarbazine were observed. Another selective RAF inhibitor, GSK2118436, has recently entered phase III trials after showing similar effectiveness in melanoma patients, and other compounds are in early clinical development
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