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In vitro model for resistance in oncogene-dependent tumors at the limit of radiological detectability

By Nina Müller, Johannes Brägelmann, Carina Lorenz, Ulrich P Michel, Dennis Plenker, Sandra Ortiz-Cuaran, Jonathan Weiss, Reinhard Büttner, Martin Peifer, Roman K Thomas, Martin L Sos, Johannes Berg

Posted 05 Sep 2019
bioRxiv DOI: 10.1101/756593

In solid tumors, the response to targeted therapy is typically short-lived, as therapy-resistant mutants can quickly expand during therapy. Here we analyze the spectrum of such resistance mutations coexisting in a large population of cancer cells. We use an iterative scheme of artificial evolution to amplify and isolate different resistance mechanisms. As a proof of concept, we apply our scheme to PC-9 cells, a human non-small cell lung cancer cell line with an activating EGFR mutation. The mechanisms we find comprise the well-known gatekeeper-mutation T790M in EGFR, a mutation in NRAS, the amplification of MET-ligand HGF, as well as induction of AKT-mTOR signaling. In this model, a combination of four drugs targeting these mechanisms prevents not only the expansion of resistant cells, but also inhibits the growth of drug-tolerant cells, which can otherwise act as a reservoir for further resistance mutations. These data suggest that a finite number of drugs specifically acting on individual resistant clones may be able to control resistance in oncogenically driven lung cancer.

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