Effective Use of PI3K and MEK Inhibitors to Treat Mutant K-Ras G12D and PIK3CA H1047R Murine Lung Cancers

By J. Engelman, Liang Chen, X. Tan, K. Crosby, A. Guimaraes, Rabi Upadhyay, Michel Maira, Kate L. McNamara, Samanthi A. Perera, Youngchul Song and 11 more. Nature Medicine, 2008

1,344 citations recorded by the source corpus.

Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-α mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110-α H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan–PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography–computed tomography, magnetic resonance imaging and microscopic examination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.

Subfields: Molecular Biology, Pathology and Forensic Medicine, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/a2f90cbb3dd682c3ef2d38bfc880f4562a0ea8fe

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Citations in the corpus

Rapamycin passes the torch: a new generation of mTOR inhibitors (2011, background): “However, concomitant inhibition of PI3K/mTOR and the mitogen-activated protein kinase (MAPK) pathway by NVPBEZ235 and the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor AZD6244 led to significant tumour regression in the KRAS transgenic mouse mode”
The Ras-ERK and PI3K-mTOR Pathways: Cross-talk and Compensation (2011, background): “Furthermore, [92, 93]chronic treatment of melanoma cells harboring activating BRAFV600E mutations can induce resistance via Raf isoform switching, upregulation of the MAPKKK COT (also called TPL2) and IGF1R-PI3K-AKT signaling pathways [94–96].”
Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset (2015, positive): “Furthermore, two inhibitor classes suggested by ACME analysis that we did not test, those targeting MTOR and PIK3CA, have also been explored in combination treatments in KRASmutant CCLs (46, 47).”
Targeting metabolic transformation for cancer therapy (2010, background): “PI3K inhibitors were also shown to reverse some of the metabolic phenotypes of cancer, leading to cancer regressio”
Targeting cancer metabolism: a therapeutic window opens (2011, background): “Interestingly, a decrease in glucose uptake — as measured by FDG–PET — has been predictive of a response to compounds that target the PI3K pathway in animal model”
Environment impacts the metabolic dependencies of Ras-driven non-small cell lung cancer (2016, background): “Because tissues with lower uptake will take longer to reach steady state, this timing was established in normal tissues, since most tumors, including Kras-driven lung tumors, exhibit elevated glucose uptake (Engelman et al., 2008).”
Targeting the phosphoinositide 3-kinase (PI3K) pathway in cancer (2009, background): “In this case, a combination of PI3K and RAF pathway inhibition by BEZ235 plus a MEK1 (MAPK kinase 1) and MEK2 inhibitor (ARRY142886; also known as ADZ6244), effectively induced tumour regression in mic”
Patient-derived Models of Acquired Resistance Can Identify Effective Drug Combinations for Cancer (2014, background): “mechanisms of resistance were identified by our approach with high specificity: For example, in a previously characterized EGFR mutant cell line with MET amplification (12), the MET inhibitors were the sole hits identified in the screen (Fig.”