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Review
. 2023 Mar 1;12(5):1936.
doi: 10.3390/jcm12051936.

A Closer Look at EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer through the Lens of Precision Medicine

Martin Sattler  1   2 , Isa Mambetsariev  3 , Jeremy Fricke  3 , Tingting Tan  3 , Sariah Liu  3 , Nagarajan Vaidehi  4 , Evan Pisick  5 , Tamara Mirzapoiazova  3 , Adam G Rock  3 , Amartej Merla  3 , Sunil Sharma  6 , Ravi Salgia  3
Affiliations
Review

A Closer Look at EGFR Inhibitor Resistance in Non-Small Cell Lung Cancer through the Lens of Precision Medicine

Martin Sattler et al. J Clin Med. .

Abstract

The development of EGFR small-molecule inhibitors has provided significant benefit for the affected patient population. Unfortunately, current inhibitors are no curative therapy, and their development has been driven by on-target mutations that interfere with binding and thus inhibitory activity. Genomic studies have revealed that, in addition to these on-target mutations, there are also multiple off-target mechanisms of EGFR inhibitor resistance and novel therapeutics that can overcome these challenges are sought. Resistance to competitive 1st-generation and covalent 2nd- and 3rd-generation EGFR inhibitors is overall more complex than initially thought, and novel 4th-generation allosteric inhibitors are expected to suffer from a similar fate. Additional nongenetic mechanisms of resistance are significant and can include up to 50% of the escape pathways. These potential targets have gained recent interest and are usually not part of cancer panels that look for alterations in resistant patient specimen. We discuss the duality between genetic and nongenetic EGFR inhibitor drug resistance and summarize current team medicine approaches, wherein clinical developments, hand in hand with drug development research, drive potential opportunities for combination therapy.

Keywords: EGFR; drug resistance; epigenetics; genetic/nongenetic; non-small cell lung cancer.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Evolution of EGFR tyrosine kinase inhibitors.
Figure 2
Figure 2
Major genetic and nongenetic escape mechanisms for acquired EGFR inhibitor resistance.
Figure 3
Figure 3
Model of genetic and nongenetic drug resistance mechanisms. Simplified model of possible (A) genetic and (B) nongenetic alteration identified in patients with therapy-related resistance to EGFR inhibitors.
See this image and copyright information in PMC

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