Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition

By A. Hata, M. Niederst, Hannah L. Archibald, María Gomez-Caraballo, Faria M. Siddiqui, Hillary E. Mulvey, Y. Maruvka, Fei Ji, H. Bhang, Viveksagar Krishnamurthy Radhakrishna and 20 more. Nature Medicine, 2016

897 citations recorded by the source corpus.

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFRT790M gatekeeper mutation can occur either by selection of pre-existing EGFRT790M-positive clones or via genetic evolution of initially EGFRT790M-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFRT790M; treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor–resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/53b6e87cf6dc45043c221048544385a62962c3ee

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In Cancer Research

1. A. Marusyk
2. K. Polyak
3. M. Janiszewska
4. R. Weinberg

In Molecular Biology

1. A. Marusyk
2. K. Polyak
3. M. Janiszewska
4. R. Weinberg
5. Zena Werb

Citations in the corpus

• Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “These cells are less sensitive to T790M targeting third generation EGFR inhibitors compared to T790M mutations on the background of therapy naïve cells (Hata et al., 2016).”
• Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, neutral): “…frequent in the advanced disease setting and may be driven by the selection of resistance cancer cells present at low frequencies prior to therapy (Bhang et al., 2015; Su et al., 2012; Turke et al., 2010) or may evolve through de novo mutations that are acquired during therapy (Hata et al., 2016).”