title: ERK inhibition overcomes acquired resistance to MEK inhibitors.
abstract: The RAS/RAF/MEK pathway is activated in more than 30% of human cancers, most commonly via mutation in the K-ras oncogene and also via mutations in BRAF. Several allosteric mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, aimed at treating tumors with RAS/RAF pathway alterations, are in clinical development. However, acquired resistance to these inhibitors has been documented both in preclinical and clinical samples. To identify strategies to overcome this resistance, we have derived three independent MEK inhibitor-resistant cell lines. Resistance to allosteric MEK inhibitors in these cell lines was consistently linked to acquired mutations in the allosteric binding pocket of MEK. In one cell line, concurrent amplification of mutant K-ras was observed in conjunction with MEK allosteric pocket mutations. Clonal analysis showed that both resistance mechanisms occur in the same cell and contribute to enhanced resistance. Importantly, in all cases the MEK-resistant cell lines retained their addiction to the mitogen-activated protein kinase (MAPK) pathway, as evidenced by their sensitivity to a selective inhibitor of the ERK1/2 kinases. These data suggest that tumors with acquired MEK inhibitor resistance remain dependent on the MAPK pathway and are therefore sensitive to inhibitors that act downstream of the mutated MEK target. Importantly, we show that dual inhibition of MEK and ERK by small molecule inhibitors was synergistic and acted to both inhibit the emergence of resistance, as well as to overcome acquired resistance to MEK inhibitors. Therefore, our data provide a rationale for cotargeting multiple nodes within the MAPK signaling cascade in K-ras mutant tumors to maximize therapeutic benefit for patients.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. hatzivassiliou.georgia@gene.com
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.forename: Bonnie
authors.initials: B
authors.lastname: Liu
authors.forename: Carol
authors.initials: C
authors.lastname: O'Brien
authors.forename: Jill M
authors.initials: JM
authors.lastname: Spoerke
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Robert
authors.initials: R
authors.lastname: Soriano
authors.forename: William F
authors.initials: WF
authors.lastname: Forrest
authors.forename: Sherry
authors.initials: S
authors.lastname: Heldens
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Karen
authors.initials: K
authors.lastname: Toy
authors.forename: Connie
authors.initials: C
authors.lastname: Ha
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.forename: Kyung
authors.initials: K
authors.lastname: Song
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.forename: Garret M
authors.initials: GM
authors.lastname: Hampton
authors.forename: John
authors.initials: J
authors.lastname: Moffat
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Mark R
authors.initials: MR
authors.lastname: Lackner
mesh_terms: D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D011905:Genes, ras; D006801:Humans; D020128:Inhibitory Concentration 50; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases