Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review
Abstract
:1. Introduction
2. EGFR Molecular Biology
Receptor Structure and Activation
3. EGFR in NSCLC
4. EGFR-Targeted Therapy in NSCLC and Mechanisms of Resistance
4.1. Tyrosine Kinase Inhibitors (TKIs)
4.1.1. Acquired Resistance to First Generation TKIs
4.1.2. Acquired Resistance to Third-Generation TKIs
4.1.3. Acquired Resistance via Downstream Activation
4.1.4. Acquired Resistance via Alternative Pathways
4.1.5. Acquired Resistance via Other Mechanisms
4.2. Monoclonal Antibody (mAb) Therapy
5. Conclusions
6. Patents
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Acronym | Definition |
AGAP3 | ArfGAP with GTPase Domain, Ankyrin Repeat and PH Domain 3 |
AGK | Acylglycerol kinase |
Akt | Protein kinase B |
AKT1 | AKT Serine/Threonine Kinase 1 |
ALK | Anaplastic lymphoma kinase |
ARMC10 | Armadillo Repeat Containing 10 |
ATP | Adenosine triphosphate |
BIM | B cell lymphoma-2-like |
BRAF | B-Raf Proto-Oncogene |
CCDC6 | Coiled-Coil Domain Containing 6 |
CDC123 | Cell Division Cycle 123 |
CEBPZ | CCAAT Enhancer Binding Protein Zeta |
CRKL | CRK like proto-oncogene |
DCBLD1 | Discoidin, CUB and LCCL Domain Containing 1 |
DOCK4 | Dedicator of cytokinesis 4 |
EGFR | Epidermal growth factor receptor |
EIF4G2 | Eukaryotic translation initiation factor 4 gamma 2 |
EMT | Epithelial to mesenchymal transition |
EPS15 | Epidermal growth factor receptor substrate 15 |
ERK | Extracellular-signal-regulated kinase |
FGFR | Fibroblast growth factor receptor |
GAB1 | Grb2 associated binding protein 1 |
GAS6 | Growth arrest specific 6 |
HER | Human epidermal growth factor receptor 2 |
IGF1R | Insulin like growth factor 1 receptor |
KIF5B | Kinesin Family Member 5B |
KRAS | Kirsten rate sarcoma viral oncogene |
LRRC71 | Leucine rich repeat containing 71 |
MAPK | Mitogen-activated protein kinase |
MEK | Mitogen-activated protein kinase kinase |
miR-21 | mircoRNA 21 |
mTOR | Mechanistic target of rapamycin |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NTRK1 | Neurotrophic Receptor Tyrosine Kinase 1 |
PDCD4 | Programmed Cell Death 4 |
PFS | Progression free survival |
PI3K | Phosphoinositide 3-kinase |
PI3KCA | PI3K catalytic subunit alpha |
PLEKHA6 | Pleckstrin homology domain containing A6 |
PTEN | Phosphatase and tensin homolog |
OS | Overall survival |
RET | Rearranged during transfection |
ROS1 | C-ros oncogene 1 |
SALL2 | Spalt like transcription factor 2 |
SCC | Squamous cell carcinoma |
SCLC | Small cell lung cancer |
STRN | Striatin |
TACC3 | Transforming acidic coiled-coil containing protein 3 |
TKI | Tyrosine kinase inhibitor |
TRIM24 | Tripartite Motif Containing 24 |
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Cancer type | Frequency of Activating Mutations of EGFR | Study | Frequency of EGFR Overexpression | Sample Size | Method of Detection | Study |
---|---|---|---|---|---|---|
NSCLC | 50% of Asian patients 10–15% of Caucasian patients | [33] | 43–89% | 96–515 | IHC a | [34,35,36,37,38,39,40,41,42,43] |
31–58% | 2972 | Meta-analysis | [44] | |||
Colorectal carcinoma (CRC) | Rare–2.33% | [45] | 51–75.5% | 99–193 | IHC | [46,47,48,49] |
Head and neck SCC b | Rare–1.72% | [45] | 45% | 115 | IHC | [50] |
92% | 24 | Southern blot hybridisation | [51] | |||
Pancreatic adenocarcinoma | Rare–0.78% | [45] | 49–69% | 32–181 | IHC | [52,53,54] |
Breast cancer | Rare–1.31% | [45] | 27% | 21,418 | Meta-analysis | [55] |
Prostate | Rare–0.82% | [45] | 31–100% | 74–98 | IHC | [56,57] |
Oesophageal SCC | Rare–2.72% | [45] | 53.6–65% | 56–152 | IHC | [58,59] |
Gastric | Rare–2.2% | [45] | 27–44% | 82–511 | IHC | [60,61] |
Hepatocellular carcinoma | Rare–1.59% | [45] | 47–68% | 53–100 | IHC | [62,63] |
Glioblastoma | 17.56% | [45] | 63% | 49 | IHC | [64] |
Ovary | Rare–0.98% | [45] | 28–33% | 80 | IHC | [65] |
Bladder | Rare–3.28% | [45] | 26.2–71% | 72–126 | IHC | [66,67] |
Renal cell carcinoma | Rare–1.16% | [45] | 21–98% | 50–175 | IHC | [68,69,70] |
Cancer Type | Tyrosine Kinase Inhibitors | Monoclonal Antibodies |
---|---|---|
NSCLC | 1st generation Gefitinib-metastatic NSCLC with EGFR exon 19 deletion or exon 21 mutation (L858R) Erlotinib-metastatic or locally advanced NSCLC with EGFR exon 19 deletion or exon 21 mutation (L858R) 2nd generation Dacomitinib-metastatic NSCLC with EGFR exon 19 deletion or exon 21 mutation (L858R) Afatinib-metastatic NSCLC with EGFR exon 19 deletion or exon 21 mutation (L858R) 3rd generation Osimertinib-metastatic EGFR T790M mutation-positive NSCLC, with progressive disease following first-line EGFR TKI therapy Olmutinib-second-line treatment of NSCLC with T790M mutation in EGFR | |
Pancreatic cancer | Erlotinib-metastatic or advanced pancreatic cancer in combination with gemcitabine | |
Breast cancer | Neratinib-HER2-overexpressing breast cancer Lapatinib-HER2-overexpressing breast cancer | |
Thyroid cancer | Vandetanib-medullary thyroid carcinoma | |
CRC | Cetuximab-metastatic KRAS-negative CRC; in combination with chemotherapy or as a single agent Panitumumab-metastatic KRAS-negative CRC; in combination with chemotherapy or as a monotherapy in patients who have failed chemotherapy | |
Head and neck- SCC | Cetuximab-in combination with radiation therapy for locally advanced disease or in combination with chemotherapy for recurrent/metastatic disease |
Effector | Prevalence | Resistance To | Mechanism |
---|---|---|---|
Germ Line Polymorphisms | |||
EGFR-T790M | Preclinical [116] | 1st Gen. TKIs | Allosteric hindrance of ATP-binding pocket, increased ATP affinity |
EGFR-V843I | 3/5 carriers developed disease [117] | 1st Gen. TKIs | Steric hindrance, associated with additional L858R mutation [118,119,120] |
BIM | Deletion in 12.9% of East Asian individuals [121] | 1st/2nd/3rd TKIs | High BIM expression correlates with tumour apoptosis and enhanced PFS/OS [122,123,124,125,126,127] |
Secondary EGFR Mutations | |||
S768I | 9/1527 cases | 1st Gen. TKIs | Attenuated BIM to reduce apoptosis, often with concurrent G719 or L858R [123,128] |
D761Y | 1/16 cases | 1st Gen. TKIs | Reduced EGFR phosphorylation with additional L858R mutation [129,130] |
T854A | 1/48 cases | 1st Gen. TKIs | Steric hindrance [131] |
L747S | 12/3648 [132] | 1st Gen. TKIs | Steric hindrance [133] |
T790M | 98/155 cases [134] | 1st/2nd Gen. TKI | Allosteric hindrance of ATP-binding pocket, increased ATP affinity [135] |
Exon20 Insertion | Asia: 67/218 [136], 23/186 Europe [137] | 1st/2nd/3rd Gen. TKIs | Conformational change inducing constitutive activation [136,137,138,139] |
L747P | Case Report | 1st/3rd Gen. TKIs | Conformational change inducing constitutive activation [140,141] |
T790M Amplification | Preclinical | 2nd Gen. TKIs | Reversible selection of amplified clone in response to TKI [142] |
C797S | 6/15 cases [143] | 3rd Gen. TKIs | Mutation in EGFR prevents osimertinib binding, 84% co-occur with multiple resistance mechanisms [144] |
G796S/R/D | 23/93 cases | 1st/3rd Gen. TKIs | Steric hindrance [145,146] |
L792F/H | 10/93 cases | 3rd Gen. TKIs | Steric hindrance, arise in trans with T790M and cis with C797S [145,147] |
L718Q | 9/93 cases [145,148] | 3rd Gen. TKIs | Steric hindrance [145] |
G724S | 4/30 cases | 3rd Gen. TKIs | A glycine-rich loop conformation prevents initial reversible TKI binding. The mutation is associated with T790M loss, mutually exclusive to C979S, and afatinib-sensitive [149,150]. |
Enhancement of Alternate Pathways | |||
CRKL | 1/11 cases [151] | 1st/2nd Gen. TKIs | Amplification, leading to downstream activation of ERK and Akt [151,152] |
MAPK | Case report | 1st Gen. TKIs | ERK overexpression [153] |
IGF1R | Preclinical | 1st/2nd Gen. TKIs | Constitutive activation of PI3K/Akt pathway [154,155] |
MET | 4/18 1st Gen-resistant cases [156], 3/5 3rd Gen-resistant cases [157] | 1st/3rd Gen. TKIs [156,157,158] | HER3-dependent PI3K activation [156] |
HER2 | 3/26 cases [159], 2/5 3rd Gen-resistant cases [157] | 1st/2nd/3rd Gen. TKIs [157,159] | Alternative receptor amplification, mutually exclusive with the T790M mutation [159] |
FGFR1 | 1/23 cases [160] | 3rd Gen. TKIs | Autocrine loop signalling [161] |
Downstream Mutations | |||
PTEN | 1/24 cases | 1st/2nd Gen. TKIs | PI3K/Akt activation via PIK3CA [162] |
PIK3CA | 5/43 cases [163] | 1st/2nd/3rd Gen. TKIs | PI3K/Akt activation [164] |
AKT1 | 3/49 cases | 1st/2nd/3rd Gen. TKIs | mTOR activation [165] |
BRAF | 2/195 cases | 3rd Gen. TKIs | MEK and ERK overexpression [166,167] |
KRAS | 3/43 cases [167], 9/38 adenocarcinoma cases [168] | 3rd Gen. TKIs | MAPK overexpression, mutually exclusive with the EGFR mutations [167,169,170] |
EMT | |||
AXL (and ligand GAS6) | 7/35 cases | 1st/2nd/3rd Gen. TKIs | EMT with vimentin overexpression [169] |
Histologic Transformation | |||
Chronic EGFR Inhibition | 5/37 1st Gen-resistance cases [170], 2 3rd Gen-resistant case studies [171] | 1st/3rd Gen. TKIs | Transformation to SCLC with EMT and potential retinoblastoma signalling [159,172,173] |
Chronic EGFR Inhibition | 1st Gen-resistant case study [172,173], 5/71 3rd Gen-resistant cases [174] | 1st/3rd Gen. TKIs | Transformation from adenocarcinoma to SCC [172,173,174] |
Transcriptional Regulation | |||
NF-κB | Statistical significance across 52 cases, Preclinical | 1st Gen. TKIs | High NF-κB activity predicted resistance via survival signalling [175] |
Epigenetics | Preclinical | 1st Gen. TKIs | miR-21 expression reducing PTEN and PDCD4 activity [176] |
Oncogene Fusion | |||
EIF4G2 | 1/32 | 1st/2nd Gen. TKIs | Treatment-resistance associated fusion to GAB1 [177] |
ALK | 108/2835 | 2nd/3rd Gen. TKI | Treatment-resistance associated fusion to EML4, STRN, CEBPZ predominantly in adenocarcinoma cases in minimal smokers [178,179] |
NTRK1 | 4/3875 cases | 2nd/3rd Gen. TKIs | Treatment-resistance associated fusion to LRRC71, PLEKHA6, RRL8, RP11 [178] |
BRAF | 1/31 with KIF5A [177], 10/3595 [180] | 2nd/3rd Gen. TKIs | Treatment-resistance associated fusion to AGAP3, AGK, ARMC10, DOCK4, EPS15, KIAA1549, SALL2, TRIM24 [180] |
RET | 6/3875 cases | 3rd Gen. TKIs | Treatment-resistance associated fusion to CCDC6, MCPA4, CDC123, KIF5B [178,181] |
ROS1 | 3/3875 cases | 3rd Gen. TKIs | Treatment-resistance associated fusion to DCBLD1 [178] |
FGFR3 | 5/32 | 3rd Gen. TKIs | Treatment-resistance associated fusion to TACC3 [177] |
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Karlsen, E.-A.; Kahler, S.; Tefay, J.; Joseph, S.R.; Simpson, F. Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review. Cells 2021, 10, 1206. https://doi.org/10.3390/cells10051206
Karlsen E-A, Kahler S, Tefay J, Joseph SR, Simpson F. Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review. Cells. 2021; 10(5):1206. https://doi.org/10.3390/cells10051206
Chicago/Turabian StyleKarlsen, Emma-Anne, Sam Kahler, Joan Tefay, Shannon R. Joseph, and Fiona Simpson. 2021. "Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review" Cells 10, no. 5: 1206. https://doi.org/10.3390/cells10051206
APA StyleKarlsen, E. -A., Kahler, S., Tefay, J., Joseph, S. R., & Simpson, F. (2021). Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review. Cells, 10(5), 1206. https://doi.org/10.3390/cells10051206