Cited by 157Protein Kinase Regulation and GTPase SignalingPI3K/AKT/mTOR signaling in cancerLung Cancer Treatments and Mutations

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Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS -Mutant Lung Cancer

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Molina-Arcas, Miriam, Hancock, David C., Sheridan, Clare, Kumar, Madhu S., Downward, Julian·2013·Cancer Discovery

DOI 10.1158/2159-8290.cd-12-0446PMC PMC3650991

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Abstract

Using a panel of non–small cell lung cancer (NSCLC) lines, we show here that MAP-ERK kinase (MEK) and RAF inhibitors are selectively toxic for the KRAS-mutant genotype, whereas phosphoinositide 3-kinase (PI3K), AKT, and mTOR inhibitors are not. IGF1 receptor (IGF1R) tyrosine kinase inhibitors also show selectivity for KRAS-mutant lung cancer lines. Combinations of IGF1R and MEK inhibitors resulted in strengthened inhibition of KRAS-mutant lines and also showed improved effectiveness in autochthonous mouse models of Kras-induced NSCLC. PI3K pathway activity is dependent on basal IGF1R activity in KRAS-mutant, but not wild-type, lung cancer cell lines. KRAS is needed for both MEK and PI3K pathway activity in KRAS-mutant, but not wild-type, lung cancer cells, whereas acute activation of KRAS causes stimulation of PI3K dependent upon IGF1R kinase activity. Coordinate direct input of both KRAS and IGF1R is thus required to activate PI3K in KRAS-mutant lung cancer cells. Significance: It has not yet been possible to target RAS proteins directly, so combined targeting of effector pathways acting downstream of RAS, including RAF/MEK and PI3K/AKT, has been the most favored approach to the treatment of RAS-mutant cancers. This work sheds light on the ability of RAS to activate PI3K through direct interaction, indicating that input is also required from a receptor tyrosine kinase, IGF1R in the case of KRAS-mutant lung cancer. This suggests potential novel combination therapeutic strategies for NSCLC. Cancer Discov; 3(5); 548–63. ©2013 AACR. See related commentary by Chen and Sweet-Cordero, p. 491 This article is highlighted in the In This Issue feature, p. 471

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Authors: Molina-Arcas, M., Hancock, D. C., Sheridan, C., Kumar, M. S., & Downward, J.
Affiliations: Authors' Affiliations: 1Signal Transduction Laboratory, Cancer Research UK London Research Institute; and 2Lung Cancer Group, Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom
Institute of Cancer Research (GB)
Corresponding author: Downward, Julian
ORCID: Hancock, David C.
Downward, Julian
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2013-05-01
Volume: 3
Issue: 5
Pages: 548-563
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-12-0446
PMC: PMC3650991
OpenAlex: W2169546036
Cited by: 157
References: 52
Citations by year: 2026: 3 · 2025: 6 · 2024: 7 · 2023: 7 · 2022: 11 · 2021: 19 · 2020: 12 · 2019: 11 · 2018: 11 · 2017: 12 · 2016: 14 · 2015: 13 · 2014: 21 · 2013: 10
FWCI: 8.67
Type: journal article
Language: en
Open access: green
europepmc.org
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Cancer Research UK (A3570, 15680)
European Commission
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Keywords: KRAS mutation, non-small cell lung cancer, IGF-1 receptor, PI3K activation, MEK inhibitors, RAF inhibitors, PI3K/AKT/mTOR inhibitors, combination therapy, Ras signaling, receptor tyrosine kinase, drug selectivity
MeSH terms: Animals, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Mice, Transgenic, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Receptor, IGF Type 1, ras Proteins, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinase Kinases, Cell Line, Tumor, Mice

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Coordinate Direct Input of Both KRAS and IGF1 Receptor to Activation of PI3 kinase in KRAS -Mutant Lung Cancer

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