Cited by 254Melanoma and MAPK PathwaysPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

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Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition

Hoeflich, Klaus P., Merchant, Mark, Orr, Christine, Chan, Jocelyn, Den Otter, Doug, Berry, Leanne, Kasman, Ian, Koeppen, Hartmut, Rice, Ken, Yang, Nai-Ying, Engst, Stefan, Johnston, Stuart, Friedman, Lori S., Belvin, Marcia·2012·Cancer Research

DOI 10.1158/0008-5472.can-11-1515

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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. Cancer Res; 72(1); 210–9. ©2011 AACR.

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BindingDB (2020) · UC San Diego · doi:10.7270/q25m68cw
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BindingDB (2020) · UC San Diego · doi:10.7270/q2fr0098
BindingDB Entry 50040273: Novel Carboxamide-Based Allosteric MEK Inhibitors: Discovery and Optimization Efforts toward XL518 (GDC-0973).
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Authors: Hoeflich, K. P., Merchant, M., Orr, C., Chan, J., Den Otter, D., Berry, L., Kasman, I., Koeppen, H., Rice, K., Yang, N.-Y., Engst, S., Johnston, S., Friedman, L. S., & Belvin, M.
Affiliations: Exelixis (United States) (US)
Authors' Affiliations: 1Genentech, Inc. and 2Exelixis, Inc., South San Francisco, California
ORCID: Hoeflich, Klaus P.
Merchant, Mark
Chan, Jocelyn
Koeppen, Hartmut
Yang, Nai-Ying
Friedman, Lori S.
Belvin, Marcia
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2012-01-01
Volume: 72
Issue: 1
Pages: 210-219
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-11-1515
OpenAlex: W2165280661
Cited by: 242
References: 36
Citations by year: 2026: 2 · 2025: 9 · 2024: 6 · 2023: 18 · 2022: 14 · 2021: 17 · 2020: 10 · 2019: 25 · 2018: 15 · 2017: 20 · 2016: 20 · 2015: 20 · 2014: 22 · 2013: 28 · 2012: 16
FWCI: 8.95
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: GDC-0941, MEK inhibitors, PI3K inhibitors, combination therapy, intermittent dosing, apoptosis, MAPK signaling, PI3K signaling, Ras signaling, BRAF-mutant cancers, KRAS-mutant cancer, Bcl-2 family proteins, tumor growth inhibition
MeSH terms: Animals, Antineoplastic Agents, Cell Division, Cell Line, Humans, Indazoles, Sulfonamides, Blotting, Western, Apoptosis, Polymorphism, Single Nucleotide, MAP Kinase Kinase Kinases, Protein Kinase Inhibitors, Mice

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Intermittent Administration of MEK Inhibitor GDC-0973 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition

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