title: Is the Canonical RAF/MEK/ERK Signaling Pathway a Therapeutic Target in SCLC?
abstract: The activity of the RAF/MEK/ERK signaling pathway is critical for the proliferation of normal and cancerous cells. Oncogenic mutations driving the development of lung adenocarcinoma often activate this signaling pathway. In contrast, pathway activity levels and their biological roles are not well established in small cell lung cancer (SCLC), a fast-growing neuroendocrine lung cancer subtype. Here we discuss the function of the RAF/MEK/ERK kinase pathway and the mechanisms leading to its activation in SCLC cells. In particular, we argue that activation of this pathway may be beneficial to the survival, proliferation, and spread of SCLC cells in response to multiple stimuli. We also consider evidence that high levels of RAF/MEK/ERK pathway activity may be detrimental to SCLC tumors, including in part by interfering with their neuroendocrine fate. On the basis of these observations, we examined when small molecules targeting kinases in the RAF/MEK/ERK pathway may be useful therapeutically in patients with SCLC, including in combination with other therapeutic agents.
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California; Department of Genetics, Stanford University, Stanford, California.
authors.forename: Sandra
authors.initials: S
authors.lastname: Cristea
authors.affiliation: Department of Pediatrics, Stanford University, Stanford, California; Department of Genetics, Stanford University, Stanford, California. Electronic address: julsage@stanford.edu.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
mesh_terms: D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009362:Neoplasm Metastasis; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D048490:raf Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Combination therapy; ERK1/2; GPCR; MAPK; SCLC; Signaling