Pre-existence and clonal selection of MET amplification in EGFR mutant NSCLC

By Alexa B. Turke, K. Zejnullahu, Yi-long Wu, Youngchul Song, D. Dias-Santagata, E. Lifshits, L. Toschi, Andrew H. Rogers, T. Mok, L. Sequist and 11 more. Cancer Cell, 2010

1,010 citations recorded by the source corpus.

Summary MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers, and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in lung cancer patients, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naïve EGFR mutant lung cancer patients who will benefit from initial combination therapy.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/eda3b98ab6b57071db71d5f8513c163ed17b651d

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

1. Nicholas McGranahan
2. Charles Swanton
3. Carlo C. Maley
4. Bert Vogelstein
5. M. Greaves
6. W. Birchmeier

In Pulmonary and Respiratory Medicine

1. Charles Swanton
2. Nicholas McGranahan

Citations in the corpus

• Targeting MET in cancer: rationale and progress (2012, background): “, but resistance can be prevented by combined inhibition of EGFR and MET, as shown in human lung, pancreatic and breast tumour xenografts (see, for example, Ref”
• SciClone: Inferring Clonal Architecture and Tracking the Spatial and Temporal Patterns of Tumor Evolution (2014, background): “Subclonal mutations can drive resistance as well, as shown in EGFR-mutant non-small cell lung cancers [27,28].”
• Intratumor heterogeneity: evolution through space and time. (2012, background): “cell lung carcinoma (NSCLC) exposure to EGFR tyrosine kinase inhibitors can result in the selection of resistant subclones harboring low-frequency mesenchymal epithelial transition factor amplification, present in the tumor before treatment (34).”
• A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity (2015, background): “Such resistant subclones are predicted to be nearly always present in lesions of sizes that can be visualized by clinical imaging techniques [29,30,31].”
• CLONAL EVOLUTION IN CANCER (2012, background): “Alternatively, subclones can have additional mutations that allow a bypass of the signalling pathway of the drug target, such as the MET proto-oncogene ( MET ) amplification in EGFR mutant lung cancer treated with EGFR kinase inhibitor”