Differences in Signaling Patterns on PI3K Inhibition Reveal Context Specificity in KRAS-Mutant Cancers.
Date
2019-08-01ICR Author
Author
Stewart, A
Coker, EA
Pölsterl, S
Georgiou, A
Minchom, AR
Carreira, S
Cunningham, D
O'Brien, ME
Raynaud, FI
de Bono, JS
Al-Lazikani, B
Banerji, U
Type
Journal Article
Metadata
Show full item recordAbstract
It is increasingly appreciated that drug response to different cancers driven by the same oncogene is different and may relate to differences in rewiring of signal transduction. We aimed to study differences in dynamic signaling changes within mutant KRAS (KRAS MT), non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma (PDAC) cells. We used an antibody-based phosphoproteomic platform to study changes in 50 phosphoproteins caused by seven targeted anticancer drugs in a panel of 30 KRAS MT cell lines and cancer cells isolated from 10 patients with KRAS MT cancers. We report for the first time significant differences in dynamic signaling between colorectal cancer and NSCLC cell lines exposed to clinically relevant equimolar concentrations of the pan-PI3K inhibitor pictilisib including a lack of reduction of p-AKTser473 in colorectal cancer cell lines (P = 0.037) and lack of compensatory increase in p-MEK in NSCLC cell lines (P = 0.036). Differences in rewiring of signal transduction between tumor types driven by KRAS MT cancers exist and influence response to combination therapy using targeted agents.
Collections
Subject
Cell Line, Tumor
Animals
Humans
Neoplasms
Phosphoproteins
Proteome
Antineoplastic Agents
Protein Kinase Inhibitors
Gene Expression Profiling
Proteomics
Signal Transduction
Gene Expression Regulation, Neoplastic
Mutation
Proto-Oncogene Proteins p21(ras)
Phosphatidylinositol 3-Kinases
Phosphoinositide-3 Kinase Inhibitors
Research team
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Computational Biology and Chemogenomics
Cancer Biomarkers
Clinical Pharmacology – Adaptive Therapy
Medicine (RMH Smith Cunningham)
Medicine Drug Development Unit (de Bono)
Prostate Cancer Targeted Therapy Group
Treatment of thoracic tumours
Language
eng
Date accepted
2019-05-10
License start date
2019-08
Citation
Molecular cancer therapeutics, 2019, 18 (8), pp. 1396 - 1404
Publisher
AMER ASSOC CANCER RESEARCH