Afatinib restrains K-RAS-driven lung tumorigenesis
Herwig P Moll1, Klemens Pranz2, Monica Musteanu3
1Department of Physiology, Center of Physiology and Pharmacology and Comprehensive Cancer Center (CCC), Medical University of Vienna, AT-1090 Vienna, Austria.
Abstract:
On the basis of clinical trials using first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), it became a doctrine that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) mutations drive resistance to EGFR inhibition in non-small cell lung cancer (NSCLC). Conversely, we provide evidence that EGFR signaling is engaged in K-RAS-driven lung tumorigenesis in humans and in mice. Specifically, genetic mouse models revealed that deletion of Egfr quenches mutant K-RAS activity and transiently reduces tumor growth. However, EGFR inhibition initiates a rapid resistance mechanism involving non-EGFR ERBB family members. This tumor escape mechanism clarifies the disappointing outcome of first-generation TKIs and suggests high therapeutic potential of pan-ERBB inhibitors. On the basis of various experimental models including genetically engineered mouse models, patient-derived and cell line-derived xenografts, and in vitro experiments, we demonstrate that the U.S. Food and Drug Administration-approved pan-ERBB inhibitor afatinib effectively impairs K-RAS-driven lung tumorigenesis. Our data support reconsidering the use of pan-ERBB inhibition in clinical trials to treat K-RAS-mutated NSCLC.
Insights
K-RAS mutations in non-small cell lung cancer (NSCLC) are driven by EGFR signaling. Pan-ERBB inhibitors like afatinib show promise for treating K-RAS-mutated NSCLC by overcoming resistance to EGFR inhibition.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Previous research established that V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-RAS) mutations confer resistance to first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC).
- This doctrine, however, overlooks the role of EGFR signaling in K-RAS-driven lung tumorigenesis.
Purpose of the Study:
- To investigate the role of EGFR signaling in K-RAS-driven lung tumorigenesis.
- To evaluate the efficacy of pan-ERBB inhibitors in overcoming resistance mechanisms in K-RAS-mutated NSCLC.
Main Methods:
- Utilized genetically engineered mouse models with K-RAS mutations and EGFR deletion.
- Employed patient-derived and cell line-derived xenografts.
- Conducted in vitro experiments and analyzed EGFR signaling pathways.
Main Results:
- EGFR signaling is integral to K-RAS-driven lung tumorigenesis.
- EGFR deletion in mouse models reduced K-RAS activity and transiently inhibited tumor growth.
- EGFR inhibition triggered resistance via non-EGFR ERBB family members, explaining the failure of first-generation TKIs.
- The pan-ERBB inhibitor afatinib demonstrated significant efficacy against K-RAS-driven lung tumorigenesis in various models.
Conclusions:
- EGFR signaling plays a crucial role in K-RAS-driven lung cancer.
- Pan-ERBB inhibitors, such as afatinib, represent a promising therapeutic strategy for K-RAS-mutated NSCLC by targeting resistance mechanisms.
- Clinical trials investigating pan-ERBB inhibition for K-RAS-mutated NSCLC are warranted.
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