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Translational Therapeutics

Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities

British Journal of Cancer volume 125, pages 1602–1611 (2021)Cite this article

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Abstract

Epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma are a frequent class of driver mutations. Single EGFR tyrosine kinase inhibitor (TKI) provides substantial clinical benefit, but almost nil radiographic complete responses. Patients invariably progress, although survival can reach several years with post-treatment therapies, including EGFR TKIs, chemotherapy or other procedures. Endeavours have been clinically oriented to manage the acquisition of EGFR TKI-resistant mutations; however, basic principles on cancer evolution have not been considered in clinical trials. For years, evidence has displayed rapidly adaptive mechanisms of resistance to selective monotherapy, posing several dilemmas for the practitioner. Strict adherence to non-small cell lung cancer (NSCLC) guidelines is not always practical for addressing the clinical progression that EGFR-mutant lung adenocarcinoma patients suffer. The purpose of this review is to highlight regulatory mechanisms and signalling pathways that cause therapy-induced resistance to EGFR TKIs. It suggests combinatorial therapies that target EGFR, as well as potential mechanisms underlying EGFR-mutant NSCLC, alerting the reader to clinical opportunities that may lead to a deeper and more durable response. Molecular reprogramming contributes to EGFR TKI resistance, and the compiled information is relevant in understanding the development of new combined targeted strategies in EGFR-mutant NSCLC.

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Fig. 1: Schematic diagram of the different signaling pathways involved in resistance to EGFR tyrosine kinase inhibitors (TKIs) driven by Protein Kinase C delta (PKCδ) and receptor tyrosine kinase recycling.
Fig. 2: Schematic overview of the Hippo signalling pathway.
Fig. 3: Crosstalk among EGFR, other receptor tyrosine kinases, and YAP minimises the effect of EGFR TKIs.

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Acknowledgements

Figures in this manuscript were created with BioRender.com.

Funding

Dr. RR reports a grant from the Spanish Association Against Cancer, AECC (PROYE18012ROSE), and funding from a European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement ELBA No. 765492.

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Authors and Affiliations

  1. Catalan Institute of Oncology, Badalona, Spain

    Rafael Rosell

  2. Oncology Institute Dr Rosell, IOR, Barcelona, Spain

    Rafael Rosell & Andrés Aguilar

  3. Clinical and Translational Oncology Group, Thoracic Oncology Unit, Institute of Oncologyt, Clínica del Country, Bogotá, Colombia

    Andrés Felipe Cardona

  4. Personalized Medicine Laboratory, Instituto Nacional de Cancerología, México City, México

    Oscar Arrieta

  5. Thoracic Oncology Unit, Instituto Nacional de Cancerología, México City, México

    Oscar Arrieta

  6. Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Masaoki Ito

  7. Germans Trias i Pujol Research Institute, Badalona, Spain

    Carlos Pedraz

  8. Biochemistry, Molecular Biology and Biomedicine Department, Universitat Autónoma de Barcelona, Bellaterra, Barcelona, Spain

    Carlos Pedraz

  9. Pangaea Oncology, Quirón-Dexeus University Institute, Barcelona, Spain

    Jordi Codony-Servat

  10. Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, Messina, Italy

    Mariacarmela Santarpia

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Contributions

Writing, review and/or revision of the manuscript: RR, AFC, OA, AA, MI, CP, JC-S and MS.

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Correspondence to Rafael Rosell.

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Rosell, R., Cardona, A.F., Arrieta, O. et al. Coregulation of pathways in lung cancer patients with EGFR mutation: therapeutic opportunities. Br J Cancer 125, 1602–1611 (2021). https://doi.org/10.1038/s41416-021-01519-2

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