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Challenges in First-Line Osimertinib Therapy in EGFR-Mutant Non-small Cell Lung Cancer: Acquired Resistance Is the Issue

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Interdisciplinary Cancer Research

Part of the book series: Interdisciplinary Cancer Research

Abstract

Non-small cell lung cancer (NSCLC), the most common form of lung cancer, accounts for 85% of all new lung cancer cases and is the leading cause of cancer-related death worldwide. NSCLC histosubtypes include adenocarcinoma, large-cell carcinoma, and squamous cell carcinoma. Cancer driving mechanisms for some NSCLC adenocarcinomas involve activating mutations of the epidermal growth factor receptor gene (EGFR), which can be selectively targeted by a number of tyrosine kinase inhibitors (TKIs). First-generation EGFR-TKIs, erlotinib and gefitinib, and then second-generation inhibitors, afatinib and dacomitinib, are designed to target EGFR-activating mutations. However, these small molecules are unresponsive to EGFR-T790M mutation. To address this obstacle, newer-generation drug design gained acceleration. Osimertinib is a third-generation EGFR-TKI that irreversibly inhibits EGFR-activating mutations as well as EGFR-T790M resistance mutation, which frequently emerges in patients treated with first- and second-generation EGFR-TKIs. While osimertinib has been initially exploited in second-line therapy, it is now standard of care in first-line treatment due to the enhanced progression-free survival (PFS) in EGFR mutant NSCLC patients. Similar to earlier EGFR-TKIs, the long-standing obstacle in osimertinib therapy is the inevitable resistance. As far as resistance mechanisms are considered, it includes EGFR mutations and aberrant activation of bypass signaling pathways and downstream signaling components. This review aims to discuss histological subtypes of lung cancer; oncogenic drivers of NSCLC; EGFR-TKIs as a treatment modality, focusing on third-generation EGFR-TKI osimertinib; diverse resistance mechanisms that include EGFR dependent and independent pathways; and possible overcoming strategies to this issue.

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Acknowledgments

Serif Senturk is a recipient of the Young Scientists Award Program of the Turkish Academy of Sciences (TUBA GEBIP 2017) and the Science Academy’s Young Scientist Awards Program (BAGEP 2019). The figures were created with BioRender.com.

Funding

This research was funded by the Scientific and Technological Research Council of Turkey (TUBITAK) via project number 119Z540.

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Authors and Affiliations

  1. Department of Genome Sciences and Molecular Biotechnology, Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir, Turkey

    Bengisu Dayanc, Sude Eris & Serif Senturk

  2. Izmir Biomedicine and Genome Center, Izmir, Turkey

    Bengisu Dayanc, Sude Eris & Serif Senturk

  3. Department of Bioinformatics and Genetics, Kadir Has University, Istanbul, Turkey

    Sude Eris

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  1. Bengisu Dayanc
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Dayanc, B., Eris, S., Senturk, S. (2022). Challenges in First-Line Osimertinib Therapy in EGFR-Mutant Non-small Cell Lung Cancer: Acquired Resistance Is the Issue. In: Interdisciplinary Cancer Research. Springer, Cham. https://doi.org/10.1007/16833_2022_54

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