title: Intermittent administration of MEK inhibitor GDC-0973 plus PI3K inhibitor GDC-0941 triggers robust apoptosis and tumor growth inhibition.
abstract: Combinations of MAP/ERK kinase (MEK) and phosphoinositide 3-kinase (PI3K) inhibitors have shown promise in preclinical cancer models, leading to the initiation of clinical trials cotargeting these two key cancer signaling pathways. GDC-0973, a novel selective MEK inhibitor, and GDC-0941, a class I PI3K inhibitor, are in early stage clinical trials as both single agents and in combination. The discovery of these selective inhibitors has allowed investigation into the precise effects of combining inhibitors of two major signaling branches downstream of RAS. Here, we investigated multiple biomarkers in the mitogen-activated protein kinase (MAPK) and PI3K pathway to search for points of convergence that explain the increased apoptosis seen in combination. Using washout studies in vitro and alternate dosing schedules in mice, we showed that intermittent inhibition of the PI3K and MAPK pathway is sufficient for efficacy in BRAF and KRAS mutant cancer cells. The combination of GDC-0973 with the PI3K inhibitor GDC-0941 resulted in combination efficacy in vitro and in vivo via induction of biomarkers associated with apoptosis, including Bcl-2 family proapoptotic regulators. Therefore, these data suggest that continuous exposure of MEK and PI3K inhibitors in combination is not required for efficacy in preclinical cancer models and that sustained effects on downstream apoptosis biomarkers can be observed in response to intermittent dosing.
authors.affiliation: Genentech, Inc and Exelixis, Inc, South San Francisco, California 94080, USA.
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.forename: Christine
authors.initials: C
authors.lastname: Orr
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chan
authors.forename: Doug
authors.initials: D
authors.lastname: Den Otter
authors.forename: Leanne
authors.initials: L
authors.lastname: Berry
authors.forename: Ian
authors.initials: I
authors.lastname: Kasman
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Ken
authors.initials: K
authors.lastname: Rice
authors.forename: Nai-Ying
authors.initials: NY
authors.lastname: Yang
authors.forename: Stefan
authors.initials: S
authors.lastname: Engst
authors.forename: Stuart
authors.initials: S
authors.lastname: Johnston
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage* / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D020930:MAP Kinase Kinase Kinases