Overview of the multifaceted resistances toward EGFR-TKIs and new chemotherapeutic strategies in non-small cell lung cancer

Biochem Pharmacol. 2022 Nov:205:115262. doi: 10.1016/j.bcp.2022.115262. Epub 2022 Oct 1.

Abstract

The role of epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) has been vastly studied over the last decade. This has led to the rapid development of many generations of EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, patients treated with third-generation TKIs (osimertinib, avitinib and rociletinib) targeting the EGFR T790M mutation have shown emerging resistances and relapses. Therefore, further molecular understanding of NSCLC mutations, bypass signalling, tumour microenvironment and the existence of cancer stem cells to overcome such resistances is warranted. This will pave the way for designing novel and effective chemotherapies to improve patients' overall survival. In this review, we provide an overview of the multifaceted mechanisms of resistance towards EGFR-TKIs, as well as the challenges and perspectives that should be addressed in strategising chemotherapeutic treatments to overcome the ever-evolving and adaptive nature of NSCLC.

Keywords: Cancer stem cells; EGFR-TKI; Lung cancer; NSCLC; Natural products.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Drug Resistance, Neoplasm
  • ErbB Receptors / genetics
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / pathology
  • Mutation
  • Neoplasm Recurrence, Local / chemically induced
  • Neoplasm Recurrence, Local / drug therapy
  • Protein Kinase Inhibitors / adverse effects
  • Tumor Microenvironment

Substances

  • ErbB Receptors
  • Protein Kinase Inhibitors
  • EGFR protein, human