title: Targeting pathways downstream of KRAS in lung adenocarcinoma.
abstract: Oncogenic KRAS activation is responsible for the most common genetic subtype of lung cancer. Although many of the major downstream signaling pathways that KRAS engages have been defined, these discoveries have yet to translate into effective targeted therapy. Much of the current focus has been directed at inhibiting the activation of RAF/MAPK and PI3K/AKT signaling, but clinical trials combining multiple different agents that target these pathways have failed to show significant activity. In this article, we will discuss the evidence for RAF and PI3K as key downstream RAS effectors, as well as the RAL guanine exchange factor, which is equally essential for transformation. Furthermore, we will delineate alternative pathways, including cytokine activation and autophagy, which are co-opted by oncogenic RAS signaling and also represent attractive targets for therapy. Finally, we will present strategies for combining inhibitors of these downstream KRAS signaling pathways in a rational fashion, as multitargeted therapy will be required to achieve a cure.
authors.affiliation: Department of Medical Oncology & Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Zehua
authors.initials: Z
authors.lastname: Zhu
authors.forename: Hadrien G
authors.initials: HG
authors.lastname: Golay
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D018631:ras Proteins
keywords: AZD6244; CYT387; KRAS; OSI-906; PI3K; RAF; RAL-GEF; autophagy; cytokines; lung cancer