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Review
. 2022 Feb;13(2):82-89.
doi: 10.1007/s13238-021-00855-6. Epub 2021 Jul 28.

Genomic instability as a major mechanism for acquired resistance to EGFR tyrosine kinase inhibitors in cancer

Bing Liu  1 , Daniela Duenas  1 , Li Zheng  1 , Karen Reckamp  2 , Binghui Shen  3
Affiliations
Review

Genomic instability as a major mechanism for acquired resistance to EGFR tyrosine kinase inhibitors in cancer

Bing Liu et al. Protein Cell. 2022 Feb.
No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The EGFR protein structure and corresponding gene exons. Exons 1–16 encode extracellular domains I-IV (orange) which can form the ligand interaction conformation. Exons 17–18 encode the transmembrane domain (blue) for connecting extracellular domains and intracellular domains. Exons 19–24 encode tyrosine kinase domain. Exon 19 deletion and exon 21 L858R mutation are original mutations that cause constant activation of tyrosine kinase activity in non-small cell lung carcinoma. Exon 20 T790M is the dominant secondary mutation acquired in response to the 1st and 2nd generation TKIs, while exon 20 C797s mutation is the secondary mutation acquired in response to the 3rd generation TKI osimertinib. Exon 25–28 encode C-terminal phosphorylation domain which mediates the interactions between the receptor and downstream substrates upon receptor activation. Abbreviations: EGF, epidermal growth factor; ECD, extracellular domain; TM, transmembrane; ICD, intracellular domain; TK, tyrosine kinase; RD, regulatory/phosphorylation domain
Figure 2
Figure 2
The network of EGFR-dependent phosphorylation cascade. This network is created based on KEGG database and current literatures. The EGFR ligands, such as EGF, TGFα, HG-EGF, Epiregulin, Betacellulin, and Amphiregulin, interact with EGFR extracellular domain to activate it via inducing its TK domain trans-autophosphorylation. The other kinases, such as SRC, are also able to phosphorylate EGFR from cytosol and be phosphorylated by activated EGFR in reverse. The expression of a number of genes is significantly changed during EGFR activation, which is accompanied with the various dynamic modifications, particularly phosphorylation. The most characterized pro-oncogenic signaling pathways phosphorylated and activated upon EGFR activation are listed at the left, including JAK/STAT, PI3K/AKT/mTOR, PLC/PKC/NFκB and MEK/ERK signaling pathways. The downstream transcription factors, including STAT3/5, p50/p65 NFκB dimer, E2F, c-MYC and c-JUN/c-FOS, play the oncogenic function to benefit cancer cell survival and proliferation. Furthermore, the stabilities of DNA replication and repair proteins, which are controlled by EGFR activation and nuclear EGFR, are illustrated at the right, including HSP70, PCNA and DNA-PK. Inhibition of EGFR TK activity with TKIs not only blocks pro-oncogenic pathways, but also DNA replication and repair pathways which are important for maintaining genomic stability. Genomic instability is the major source for resistance mutation generation, which might reduce EGFR TKI efficiency and activate the receptors from bypass signaling pathways, such as MET and AXL receptors, to further support cancer progression. Thus, maintaining genomic stability, especially by protecting the expression and stability of DNA replication and repair components, may forestall the generation and evolution of tumor cell mutations, ultimately reducing drug resistance. Abbreviations: SRC, Proto-oncogene tyrosine-protein kinase Src; JAK, Janus kinase; STAT3/5, Signal transducer and activator of transcription3/5; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PTEN, Phosphatase and tensin homolog; PIP3, Phosphatidylinositol (3,4,5)-trisphosphate; PDK, 3-phosphoinositide-dependent protein kinase; PKB, Protein kinase B; AKT, v-Akt murine thymoma viral oncogene homolog; mTOR, Mechanistic target of rapamycin kinase; p70S6K, Ribosomal protein S6 kinase; eIF-4EBP, Eukaryotic translation initiation factor 4E binding protein; EIF4E, Eukaryotic translation initiation factor 4E; S6, Ribosomal protein S6; PLC, Phospholipase C; IP3, Inositol trisphosphate; DAG, Diacylglycerol; PKC, Protein kinase C; RINCK1, E3 ligase RING finger protein that interacts with C kinase 1; NEMO, Inhibitor of nuclear factor kappa B kinase regulatory subunit gamma; IKK, inhibitor of nuclear factor kappa B kinase subunit; CARMA3, Caspase recruitment domain family member 10; BCL-10, B cell lymphoma protein 10; MALT1, Mucosa-associated lymphoid tissue lymphoma translocation gene 1; TRAF6, TNF receptor associated factor 6; p50, NFκB Subunit 1; p65, RELA proto-oncogene, NFκB subunit; SHC, SHC adaptor protein 1; GRB2, Growth factor receptor bound protein 2; SOS, Ras/Rac guanine nucleotide exchange factor; RAS, Rat sarcoma virus; RAF, Rapidly accelerated fibrosarcoma; MEK, Mitogen-activated protein kinase kinase; ERK, Extracellular signal-regulated kinase; RSK, MAP kinase-activated protein kinase; MNK, ATPase copper transporting alpha; CCND1, Cyclin D1; CDK, Cyclin dependent kinase; E2F, E2F transcription factor; RB1, RB transcriptional corepressor 1; ELK-1, ETS transcription factor; c-MYC, Myc proto-oncogene protein; c-JUN, Transcription factor AP-1; c-FOS, AP-1 transcription factor subunit; HSP70, Heat shock 70 kDa protein; SEC61, Translocon subunit alpha 1; PCNA, Proliferation cell nuclear antigen; DNA-PK, DNA-dependent protein kinase; FEN1, Flap endonuclease 1; ER, Endoplasmic reticulum
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