title: Epithelial tissue hyperplasia induced by the RAF inhibitor PF-04880594 is attenuated by a clinically well-tolerated dose of the MEK inhibitor PD-0325901.
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.
authors: Shubha Bagrodia, Oncology Research Unit, Pfizer Worldwide Research and Development, La Jolla Laboratories, 10724 Science Center Drive, San Diego, CA 92121, USA. shubha.bagrodia@pfizer.com
authors: Vince R
authors: VR
authors: Torti
authors: Donald
authors: D
authors: Wojciechowicz
authors: Wenyue
authors: W
authors: Hu
authors: Annette
authors: A
authors: John-Baptiste
authors: Winston
authors: W
authors: Evering
authors: Gabriel
authors: G
authors: Troche
authors: Lisa D
authors: LD
authors: Marroquin
authors: Tod
authors: T
authors: Smeal
authors: Shinji
authors: S
authors: Yamazaki
authors: Cynthia L
authors: CL
authors: Palmer
authors: Leigh Ann
authors: LA
authors: Burns-Naas
authors: Shubha
authors: S
authors: Bagrodia
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D006965:Hyperplasia; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001549:Benzamides; D016209:Interleukin-8; C578611:PF-04880594; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C506614:mirdametinib; D004159:Diphenylamine; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases