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Review
. 2021 Mar 9:14:301-317.
doi: 10.2147/PGPM.S242045. eCollection 2021.

Tackling Drug Resistance in EGFR Exon 20 Insertion Mutant Lung Cancer

Laura Pacini #  1 , Andrew D Jenks #  1 , Simon Vyse #  1 , Christopher P Wilding  1 , Amani Arthur  1 , Paul H Huang  1
Affiliations
Review

Tackling Drug Resistance in EGFR Exon 20 Insertion Mutant Lung Cancer

Laura Pacini et al. Pharmgenomics Pers Med. .

Abstract

Insertion mutations in exon 20 (Ex20ins) of the epidermal growth factor receptor (EGFR) gene are the largest class of EGFR mutations in non-small cell lung cancer (NSCLC) for which there are currently no approved targeted therapies. NSCLC patients with these mutations do not respond to clinically approved EGFR tyrosine kinase inhibitors (TKIs) and have poor outcomes. A number of early phase clinical trials are currently underway to evaluate the efficacy of a new generation of TKIs that are capable of binding to and blocking Ex20ins. Although these agents have shown some clinical activity, patient responses have been restricted by dose-limiting toxicity or rapid acquisition of resistance after a short response. Here we review the current understanding of the mechanisms of resistance to these compounds, which include on-target EGFR secondary mutations, compensatory bypass pathway activation and acquisition of an EMT phenotype. Taking lessons from conventional EGFR inhibitor therapy in NSCLC, we also consider other potential sources of resistance including the presence of drug-tolerant persister cells. We will discuss therapeutic strategies which have the potential to overcome different forms of drug resistance. We conclude by evaluating recent technological developments in drug discovery such as PROTACs as a means to better tackle TKI resistance in NSCLC harbouring Ex20ins mutations.

Keywords: EGFR; PROTACs; drug resistance; exon 20 insertions; lung cancer; poziotinib.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Therapeutic approaches to target EGFR Ex20ins NSCLC in clinical trials. Several approaches with distinct mechanisms are being assessed in clinical trials to target EGFR Ex20ins NSCLC, which are refractory to current clinically approved EGFR inhibitors. Small molecule tyrosine kinase inhibitors with the capacity to target the EGFR Ex20ins (Ex20ins TKI) can inhibit kinase catalytic activity. The bispecific EGFR-MET antibody amivantamab binds to both receptor tyrosine kinases which can result in receptor internalisation and downmodulation of oncogene expression on the cell surface. The Hsp90 inhibitor luminespib can inhibit the Hsp90 chaperone system which is co-opted by mutant EGFR Ex20ins to prevent ubiquitin-mediated protein degradation.
Figure 2
Figure 2
Mechanisms of EGFRex20ins TKI resistance. Evidence from the use of poziotinib in patients and in pre-clinical models suggests drug resistance can be driven by (A) acquisition of secondary on-target mutations in EGFR or (B) mutations or amplification in other oncogenic pathway proteins that result in activation of compensatory bypass pathways including the PI3K/AKT pathway, RAS/MAPK pathway, alternative RTKs and cell cycle genes.
Figure 3
Figure 3
Comparison of tyrosine kinase inhibitor, PROTAC and therapeutic monoclonal antibodies mechanism of action. (A) TKIs bind to the kinase domain of the receptor which inhibits receptor phosphorylation and activation. Upon acquisition of drug resistance either develops on-target mutations or activate compensatory bypass pathways. (B) PROTACs degrade tyrosine kinase receptors through protein ubiquitination and receptor degradation. The degradation of the receptor is thought to minimize the activation of compensatory bypass pathways. (C) A combination of three monoclonal antibodies can target T790M and C797S mutant EGFR tumors. Cetuximab (EGFR), trastuzumab (HER2) and mAb33 (HER3) when used together were shown to suppress HER2, HER3, MET and AXL compensatory bypass pathway activation.
Figure 4
Figure 4
Proposed model of drug tolerant persister cell evolution. Under drug pressure a subpopulation of transient drug tolerant persister cells can emerge through epigenetic mechanisms. This transient DTP population can acquire permanent genetic modifications which allows for the emergence of a drug tolerant population. The transcriptionally dependent state of persister cells induced by targeted therapy can be exploited by the treatment with THZ1 which blocks transcriptional responses, promoting cancer cell death. However, THZ1 treatment in combination with erlotinib suppresses the expression of the UFMylation pathway components which can trigger a protective unfolded protein response associated with tolerable levels of ER stress and cell survival.
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