Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

CANCER THERAPY

Resistance is futile with fourth-generation EGFR inhibitors

Nature Cancer volume 3, pages 381–383 (2022)Cite this article

Subjects

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have revolutionized the treatment of EGFR-mutant non-small cell lung cancer; however, secondary resistance limits their efficacy, emphasizing the need for newer approaches. A study now shows preclinical development of allosteric EGFR inhibitors that overcome acquired therapy resistance.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in western countries1. It has been found that 10–15% of patients with NSCLC harbor activating mutations of EGFR, a member of the human epidermal growth factor receptor (HER) family2. These genetic events cause tumor cells to become dependent on constitutively active EGFR signaling, which mediates proliferation and survival processes3. These genetic alterations occur in the tyrosine kinase domain (exons 19 and 21) of the receptor, and have been used as pharmacological targets for tyrosine kinase inhibitors (TKI) over the past 18 years. During this time, three generations of EGFR TKIs have been developed to overcome acquired on-target resistance mechanisms4. In this issue of Nature Cancer, To et al.5 report the characterization of JBJ-09-063, an allosteric EGFR inhibitor that is effective as a single agent in models harboring EGFR L858R, T790M and C797S mutations, as well as other rarer mutations that confer resistance to osimertinib, with superior pharmacodynamic properties compared to its parent compound JBJ-04-125-02. Moreover, JBJ-09-063 shows a stronger effect on L858R, suggesting the potential to overcome worse overall survival (OS) and progression-free survival (PFS) than osimertinib, as reported in patients with exon-19 deletions5.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Mechanisms of resistance to allosteric EGFR inhibitors.

References

  1. Siegel, R. L. et al. CA Cancer J. Clin. 72, 7–33 (2022).

    Article  Google Scholar 

  2. Midha, A., Dearden, S. & McCormack, R. Am. J. Cancer Res. 5, 2892–2911 (2015).

    PubMed  PubMed Central  Google Scholar 

  3. Lynch, T. J. et al. N. Engl. J. Med. 350, 2129–2139 (2004).

    Article  CAS  Google Scholar 

  4. Passaro, A. et al. Nat. Cancer 2, 377–391 (2021).

    Article  CAS  Google Scholar 

  5. To, C. et al. Nat. Cancer https://doi.org/10.1038/s43018-022-00351-8 (2022).

  6. Ramalingam, S. S. et al. N. Engl. J. Med. 382, 41–50 (2020).

    Article  CAS  Google Scholar 

  7. Mok, T. S. et al. N. Engl. J. Med. 376, 629–640 (2017).

    Article  CAS  Google Scholar 

  8. Igawa, S. et al. Cancer Manag. Res. 11, 4883–4892 (2019).

    Article  CAS  Google Scholar 

  9. Jia, Y. et al. Nature 534, 129–132 (2016).

    Article  CAS  Google Scholar 

  10. To, C. et al. Cancer Discov. 9, 926–943 (2019).

    Article  CAS  Google Scholar 

  11. Leahy, D. J. Cell 142, 513–515 (2010).

    Article  CAS  Google Scholar 

  12. Rodrik-Outmezguine, V. S. et al. Nature 534, 272–276 (2016).

    Article  CAS  Google Scholar 

  13. Mullard, A. Nat. Rev. Drug Discov. 20, 806 (2021).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Michelangelo Marasco & Sandra Misale

Authors
  1. Michelangelo Marasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sandra Misale
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandra Misale.

Ethics declarations

Competing interests

S.M. has served as a consultant for Boehringer Ingelheim. M.M. declares no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marasco, M., Misale, S. Resistance is futile with fourth-generation EGFR inhibitors. Nat Cancer 3, 381–383 (2022). https://doi.org/10.1038/s43018-022-00365-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43018-022-00365-2

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing