TY - JOUR
T1 - Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer
AU - Molina-Arcas, Miriam
AU - Moore, Christopher
AU - Rana, Sareena
AU - Van Maldegem, Febe
AU - Mugarza, Edurne
AU - Romero-Clavijo, Pablo
AU - Herbert, Eleanor
AU - Horswell, Stuart
AU - Li, Lian Sheng
AU - Janes, Matthew R.
AU - Hancock, David C.
AU - Downward, Julian
N1 - Funding Information: This work was supported by funding to J.D. from the Francis Crick Institute-which receives its core funding from Cancer Research UK (FC001070), the UK Medical Research Council (FC001070), and the Wellcome Trust (FC001070)-from the European Research Council Advanced Grant RASTARGET, and from a Wellcome Trust Senior Investigator Award 103799/Z/14/Z. Publisher Copyright: Copyright © 2019 The Authors.
PY - 2019/9/18
Y1 - 2019/9/18
N2 - KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.
AB - KRAS represents an excellent therapeutic target in lung cancer, the most commonly mutated form of which can now be blocked using KRAS-G12C mutant-specific inhibitory trial drugs. Lung adenocarcinoma cells harboring KRAS mutations have been shown previously to be selectively sensitive to inhibition of mitogen-activated protein kinase kinase (MEK) and insulin-like growth factor 1 receptor (IGF1R) signaling. Here, we show that this effect is markedly enhanced by simultaneous inhibition of mammalian target of rapamycin (mTOR) while maintaining selectivity for the KRAS-mutant genotype. Combined mTOR, IGF1R, and MEK inhibition inhibits the principal signaling pathways required for the survival of KRAS-mutant cells and produces marked tumor regression in three different KRAS-driven lung cancer mouse models. Replacing the MEK inhibitor with the mutant-specific KRAS-G12C inhibitor ARS-1620 in these combinations is associated with greater efficacy, specificity, and tolerability. Adding mTOR and IGF1R inhibitors to ARS-1620 greatly improves its effectiveness on KRAS-G12C mutant lung cancer cells in vitro and in mouse models. This provides a rationale for the design of combination treatments to enhance the impact of the KRAS-G12C inhibitors, which are now entering clinical trials.
UR - http://www.scopus.com/inward/record.url?scp=85072402823&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/scitranslmed.aaw7999
DO - https://doi.org/10.1126/scitranslmed.aaw7999
M3 - Article
C2 - 31534020
SN - 1946-6234
VL - 11
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 510
M1 - eaaw7999
ER -