Data from Characterizing Evolutionary Dynamics Reveals Strategies to Exhaust the Spectrum of Subclonal Resistance in EGFR-Mutant Lung Cancer

• DOI: 10.1158/0008-5472.c.6769301.v1
• Publication Date: 2023-08-01T08:41:44Z
• Authors: Nina Müller; Carina Lorenz; Jenny Ostendorp; Felix S. Heisel; Ulrich P. Friese; Maria Cartolano; Dennis Plenker; Hannah Tumbrink; Alena Heimsoeth; Philipp Baedeker; Jonathan Weiss; Sandra Ortiz-Cuaran; Reinhard Büttner; Martin Peifer; Roman K. Thomas; Martin L. Sos; Johannes Berg; Johannes Brägelmann

<div>Abstract<p>The emergence of resistance to targeted therapies restrains their efficacy. The development rationally guided drug combinations could overcome this currently insurmountable clinical challenge. However, our limited understanding the trajectories that drive outgrowth resistant clones in cancer cell populations precludes design forestall resistance. Here, we propose an iterative treatment strategy coupled with genomic profiling and genome-wide CRISPR activation screening systematically extract define preexisting subpopulations EGFR-driven lung line. Integrating these modalities identifies several mechanisms, including YAP/TAZ signaling by <i>WWTR1</i> amplification, estimates associated cellular fitness for mathematical population modeling. These observations led a combination therapy eradicated large line exhausting spectrum mechanisms. small fraction cells was able enter reversible nonproliferative state tolerance. This subpopulation exhibited mesenchymal properties, NRF2 target gene expression, sensitivity ferroptotic death. Exploiting induced collateral GPX4 inhibition clears drug-tolerant leads tumor eradication. Overall, experimental <i>in vitro</i> data theoretical modeling demonstrate why mono- dual will likely fail sufficiently limit long-term Our approach is not tied particular driver mechanism can be used assess ideally exhaust landscape different types therapies.</p>Significance:<p>Unraveling persister facilitates rational multidrug or sequential therapies, presenting explore treating EGFR-mutant cancer.</p></div>