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EGFR tyrosine kinase inhibitors and multidrug resistance: perspectives

Nicola A Colabufo1, Marialessandra Contino, Mauro Niso

  • 1Dipartimento Farmacochimico, Universita degli Studi di Bari, A Moro, via Orabona, 4, 70125 Bari, Italy. colabufo@farmchim.uniba.it

Frontiers in Bioscience (Landmark Edition)
|January 4, 2011
PubMed

Insights

This review details how epidermal growth factor receptor (EGFR) inhibitors, particularly tyrosine kinase inhibitors (TKIs), face resistance due to specific mutations and transporter proteins. Strategies to overcome this drug resistance and potential diagnostic applications are discussed.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Epidermal growth factor receptor (EGFR) inhibitors, especially tyrosine kinase inhibitors (TKIs), are crucial in cancer therapy.
  • Acquired resistance to these drugs is a significant clinical challenge, limiting treatment efficacy.
  • Multidrug resistance (MDR) mechanisms, including transporter proteins, contribute to treatment failure.

Purpose of the Study:

  • To provide an evidence-based update on the mechanisms of resistance to EGFR inhibitors, focusing on TKIs.
  • To review the role of specific EGFR mutations and transporter proteins in TKI resistance.
  • To discuss strategies for overcoming drug resistance and potential diagnostic applications of TKIs.

Main Methods:

  • Literature review of studies investigating EGFR inhibitor resistance mechanisms.
  • Analysis of the roles of ATP-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).
  • Examination of different subtypes of EGFR mutations (kinase domain vs. truncating mutations) and their impact on downstream signaling pathways (MAPK, PI3K/Akt, STAT).

Main Results:

  • P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are implicated as key transporters in TKI resistance.
  • Two main categories of EGFR mutations contribute to resistance: those in the tyrosine kinase domain (exons 18-21) leading to TKI failure, and truncating mutations (exons 2-7) affecting downstream pathways.
  • Non-small cell lung cancer (NSCLC) is characterized by kinase domain mutations, often associated with TKI failure.

Conclusions:

  • Understanding the interplay between EGFR mutations and drug efflux pumps is critical for managing TKI resistance.
  • Strategies to overcome multidrug resistance (MDR) and bypass kinase domain mutations are essential for improving patient outcomes.
  • First-generation TKIs show potential as radiotracers for diagnosing tumors overexpressing P-gp and BCRP via PET/SPECT imaging.

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