The Role of Proteomics and Phosphoproteomics in the Discovery of Therapeutic Targets and Biomarkers in Acquired EGFR-TKI-Resistant Non-Small Cell Lung Cancer
Abstract
:1. Introduction
2. EGFR-TKIs
2.1. First- and Second-Generation EGFR-TKIs
2.2. Third-Generation EGFR-TKIs
3. Proteomics in the Study of Molecular Mechanisms of Acquired Resistance of EGFR-TKI in NSCLC
3.1. Bypass and Downstream Pathway Activation
3.1.1. Aberrant Expression of RTK
3.1.2. SRC Signaling Pathway
3.1.3. FGFR-Akt
3.1.4. FAK Signaling
3.1.5. PI3K/Akt/mTOR and MAPK/Erk Signaling
3.2. Histological Transformation
3.3. Miscellaneous Pathway
3.3.1. Autophagy
3.3.2. Antigen Presenting Pathway
3.3.3. Metabolism
3.3.4. Post-Translational Modification of EGFR
4. Proteomics in Serum Biomarker Discovery of EGFR-TKI Resistance in NSCLC
Study | Samples | Discovery Cohort/Training Set | Sampling Time | EGFR-TKI | Protein Biomarker/ Biomarker | Sample Pre-Processing | Proteomic Technique | Finding |
---|---|---|---|---|---|---|---|---|
Hsiao 2020 [67] | Pleural effusion | Advanced lung adenocarcinoma with EGFR mutation with differential response to EGFR-TKI (N = 23) and patients with tuberculosis (N = 10) | - | Gefitinib, Erlotinib, Afatinib | Cadherin-3 (CDH3) | Multiple Affinity Removal System (MARS) Affinity Column | iTRAQ/2D LC MS-MS | [EGFR-TKI response predictive marker, Prognostic marker] The PE level of soluble CDH3 (sCDH3) was increased in patients with resistance. The altered sCDH3 serum level reflected the efficacy of EGFR-TKI after 1 month of treatment (n = 43). Baseline sCDH3 was significantly associated with PFS and OS in patients with ADC after EGFR-TKI therapy (n = 76). Moreover, sCDH3 was positively associated with tumor stage in non–small cell lung cancer (n = 272). |
Shang 2019 [66] | Serum | Advanced lung adenocarcinoma with EGFR mutation who had partial response after 2 cycles of first-line erlotinib (N = 9) and heathy control (N = 9) | Baseline, PR, and PD) | Erlotinib | Isoform 2 of fibrinogen alpha chain (FGA2) | - | Antibody microarray/immunoprecipitation/ LC-MS/MS (Q-Orbitrap) | [EGFR-TKI response predictive marker] serum FGA2 level was correlated with EGFR-TKI response (p < 0.05). |
Zhao 2013 [65] | Serum | Advanced lung adenocarcinoma with long PFS (N = 18) | Baseline and PD | Erlotinib, Gefitinib | a1-antitrypsin (AAT) | Liquid chromatographic column | 2D-DIGE/MALDI-TOF/TOF | [EGFR-TKI response predictive marker] AAT was upregulated in PD compared with baseline, with an average ratio of 1.68 (P¼0.0017), and Western blot analysis showed that AAT was downregulated in PR. |
Milan 2012 [70] | Serum | Advanced NSCLC patients | Baseline | Gefitinib | Serum amyloid A protein 1 (SAA1) | Agilent Multiple Affinity Removal System | 2DE/MALDI-TOF/LC-MS/MS (Q-TOF) | [EGFR-TKI response predictive marker] |
Buttigliero 2019 [76] | Serum | Advanced NSCLC treated in the second or third line with tivantinib plus erlotinib (T+E) compared with placebo plus erlotinib (P+E) | Baseline | Erlotinib | Proteomic spectra | VeriStrat | [EGFR-TKI response predictive marker, Prognostic marker] Phase III clinical trial | |
Wu 2013 [78] | Serum | Advanced NSCLC patients (N = 24) | Baseline | Erlotinib, Gefitinib | Serum proteomic classifier | MB-WCX kits | MALDI-TOF | [EGFR-TKI response predictive marker] |
Lazzari 2012 [69] | Plasma | NSCLC Patients (N = 111) | baseline, after 1 month and concomitantly with CT scan evaluation performed every other month until withdrawal from treatment with EGFR TKIs for either toxicity or progression. | Gefitinib | Proteomic spectra | - | MALDI-TOF (Veristrat) | [EGFR-TKI response predictive marker] |
Taguchi 2007 [68] | Serum | NSCLC patients (N = 139) | Baseline | Erlotinib, Gefitinib | Proteomic spectra | - | MALDI-TOF | [EGFR-TKI response predictive marker] This MALDI MS algorithm was not merely prognostic but could classify NSCLC patients for good or poor outcomes after treatment with EGFR TKIs. This algorithm may thus assist in the pretreatment selection of appropriate subgroups of NSCLC patients for treatment with EGFR TKIs. |
5. Clinical Applications
5.1. AXL
5.2. SRC
5.3. PI3K Signaling Pathway
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AAT | Alpha-1-ntitrypsin |
2DE | Two-dimensional gel electrophoresis |
ABL1 | Tyrosine-protein kinase ABL1 |
ACK-1 | Activated CDC42 kinase 1 |
AKT | Protein kinase B |
ALOX5 | Arachidonate 5-lipoxygenase |
ANXA2 | Annexin A2 |
ATP | Adenosine triphosphate |
BCAR3 | Breast cancer anti-estrogen resistance protein 3 |
Bcl-2 | B-cell lymphoma 2 |
BIM | B cell lymphoma-2-like 11 |
c-MET | Tyrosine-protein kinase Met |
C797S | The mutation substitutes a cysteine with a serine at position 797 |
CAF | Cancer-associated fibroblast |
CASL | Integrin signaling adaptor |
CDH1 | Epithelial cadherin |
CNS | Central nervous system |
E-cadherin | Epithelial cadherin |
EGFR | Epidermal growth factor receptor |
eIF3c | Eukaryotic Translation Initiation Factor 3 Subunit C |
EMT | Epithelial to mesenchymal transition |
EPHB1 | EPH receptor B1 |
ERAP | Endoplasmic reticulum aminopeptidase |
ErbB | A family of proteins contains four receptor tyrosine kinases |
ERK | Extracellular signal-regulated kinase |
exon 19 delins | Exon 19 deletion-insertions |
exon 19dels | Exon 19-microdeletions |
FAK | Focal adhesion kinase |
FGA2 | Isoform 2 of fibrinogen alpha chain |
FGFR | Fibroblast growth factor receptor 1 protein |
FOXM1 | Forkhead box protein M1 |
FRS-2 | Fibroblast growth factor receptor substrate 2 |
HER1 | Human epidermal growth factor receptor 1 |
HER2 | Human epidermal growth factor receptor 2 |
HER4 | Human epidermal growth factor receptor 4 |
HGF | Hepatocyte growth factor |
HLA | Human leukocyte antigen |
HMGA2 | High-mobility group AT-hook 2 |
IGF | Insulin-like growth factor |
IGFR2 | Insulin-like growth factor 2 receptor |
IL-6 | Interleukin-6 |
IRS2 | Insulin receptor substrate 2 |
ITGAV | Integrin alpha V |
iTRAQ | Isobaric tags for relative and absolute quantitation |
L858R | The mutation substitutes a leucine with an arginine at position 858 |
LAMA5 | Laminin α5 |
LOXL2 | Lysyl oxidase homolog 2 |
MALDI-TOF | Matrix-Assisted Laser Desorption/Ionization Time-of-Flight |
MAPK | Mitogen-activated protein kinase |
MID1 | A protein that belongs to the Tripartite motif family |
mOS | Median overall survival |
mPFS | Median progression-free survival |
mTOR | Mammalian target of rapamycin |
NNMT | Nicotinamide N-methyltransferase |
OPN | Osteopontin |
ORR | Objective response rate |
PBC | Platinum-based chemotherapy |
PD | Progressive disease |
PE | Pleural effusion |
PFS | Progression-free survival |
PI3K | Phosphoinositide 3-kinase |
PRAS40 | Proline-rich Akt substrate of 40 kDa |
PR | Partial response |
PTPN11 | Tyrosine-protein phosphatase non-receptor type 11 |
RGD | Arginine-glycine-aspartic acid |
RPPA | Reverse Phase Protein Array |
RTK | Receptor tyrosine kinase |
SAC | Spindle assembly checkpoint |
sCDH3 | Soluble cadherin-3 |
SFK | Src family kinases are composed of 10 proteins: Src, Frk, Lck, Lyn, Blk, Hck, Fyn, Yrk, Fgr, and Yes |
SILAC | Stable isotope labeling by amino acids in cell culture |
SIRT1 | Sirtuin 1 |
SLC1A5 | Solute carrier family 1 member 5 |
SSA1 | Serum amyloid A protein 1 |
T790M | The mutation substitutes a threonine with a methionine at position 790 |
TAP1 | Transporter associated with antigen processing 1 |
TKI | Tyrosine kinase inhibitor |
VCL | Vinculin |
WNK1 | Lysine deficient protein kinase 1 |
YAP | Yes-associated protein |
ZEB1 | Zinc Finger E-Box Binding Homeobox 1 |
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Generation | Drug | Chemical Classification | Targets | Clinical Application for NSCLC | Approved Years |
---|---|---|---|---|---|
First generation EGFR-TKIS | Gefitinib | quinazolinamine | EGFR | Unselected NSCLC First-line therapy: Metastatic EGFR-sensitizing mutant | 2002 2015 |
Erlotinib | quinazolinamine | EGFR, EGFR (del19), EGFR (L858R) | Locally advanced or metastatic NSCLC First-line therapy: Advanced EGFR-sensitizing mutant | 2004 2013 | |
Icotinib | quinazolinamine | EGFR (L858R) | Locally advanced or metastatic NSCLC First-line therapy: Metastatic EGFR-sensitizing mutant | 2011 2014 | |
Second generation EGFR-TKIS | Afatinib | quinazolinamine | EGFR, EGFR (L858R/T790M), HER2, HER4 | Metastatic EGFR-sensitizing mutant | 2013 |
Dacomitinib | quinazolinamine | EGFR, EGFR (del19), EGFR (L858R), HER2, HER4 | First-line therapy: Metastatic EGFR-sensitizing mutant | 2018 | |
Third generation EGFR-TKIS | Osimertinib | aminopyrimidines | EGFR, EGFR (del19), EGFR (L858R), EGFR (T790M) | EGFR-T790M mutation First-line therapy: Metastatic EGFR-sensitizing mutant Adjuvant therapy | 2015 2018 2020 |
Almonertinib | aminopyrimidines | EGFR (del19), EGFR (L858R), EGFR (T790M) | EGFR-T790M mutation | 2020 | |
Furmonertinib | aminopyrimidines | EGFR (del19), EGFR (L858R), EGFR (T790M) | Locally advanced or metastatic NSCLC with EGFR T790M mutation | 2021 |
Study | Dysregulated Proteins | Altered Pathways | Mechanisms | EGFR-TKIs (Generation) | Samples | Proteomic and Quantitation Techniques |
---|---|---|---|---|---|---|
Wang 2022 [40] | Nicotinamide N-methyltransferase (↑) | Glycolysis (↑) | Miscellaneous | Gefitinib (1st) | PC9 vs. PC9/GR | LC-MS/MS, iTRAQ-labeling |
Hou 2022 [41] | phosphorylated activation loops of SRC family proteins, such as SRC, ACK, FER, and FYN (↑) | The MAPK/ERK pathway, PI3K/AKT signaling (↑) | Bypass and downstream pathway activation | Osimertinib (3rd) | H1975 vs. H1975OsiR | Phosphopeptide Enrichment LC-MS/MS |
Li 2022 [42] | Laminin α5, FAK (↑) | PI3K-AKT, Laminin α5/FAK signaling (↑) | Bypass and downstream pathway activation | Osimertinib (3rd) | PC9/GR vs. PC9/GROsiR | LC-MS/MS |
Qi 2021 [43] | HLA class I-presented immunopeptidome, antigen presentation core complex (e.g., TAP1 and ERAP1/2), and immunoproteasome (↓) | immunoproteasome and autophagy cascades (↓) | Miscellaneous | Osimertinib (3rd) | PC9 vs. PC9/OsiR H1975 vs. H1975/OsiR | LC-MS/MS, SILAC labeling |
Terp 2021 [44] | The receptor tyrosine kinase AXL, FGFR1, PRAS40 (↑) | FGFR1-Akt pathway (↑) | Bypass and downstream pathway activation | Erlotinib (1st) | HCC827 vs. HCC827/ER | LC-MS/MS, iTRAQ-labeling |
Liu 2021 [45] | SLC1A5 (↑) | PI3K-AKT (↑) | Bypass and downstream pathway activation | Almonertinib (3rd) | H1975 cell treated with Almonertinib vs. blank control | LC-MS |
Zang 2021 [46] | Too many (↑) | PI3K/AKT pathways, EMT (↑) | Bypass, downstream pathway activation, and histological transformation | Osimertinib or Rociletinib (3rd) | H1975 vs. H1975/OsiR H1975 vs. H1975/COR | LC-MS/MS, SILAC labeling |
Wang 2020 [47] | AXL (↑) | EMT, cytoskeletal reorganization, and migratory and invasive properties. (↑) | Histological transformation | 3rd Generation | H1975 vs. H1975-MS35 | LC-MS/MS, iTRAQ-labeling |
Fu 2020 [48] | Osteopontin (↑) | integrin αVβ3/FAK signaling pathway (↑) | Bypass and downstream pathway activation | Gefitinib (1st) | PC9 vs. PC9/GR HCC827 vs. HCC827/GR | Proteome profiler array |
Nilsson 2020 [49] | AXL and ZEB1 (↑) E-cadherin and 𝛽-catenin, c-MET (↓) | EMT, cytoskeletal reorganization, and migratory and invasive properties. (↑) | Histological transformation | Erlotinib (1st) | HCC827 vs. HCC827/ER HCC4006 vs. HCC4006/ER | Reverse phase protein array |
Shintani 2018 [50] | eukaryotic translation initiation factor 3 subunit C (eIF3c) (↑) | Autophagy (↑) | Miscellaneous | Erlotinib (1st) | PC9 vs. PC9/ER | LC-MS/MS |
Waniwan 2018 [51] | Glycoprotein and fucosylated glycans (↑) | - | Miscellaneous | Gefitinib (1st) | PC9 vs. PC9-IR | lectin−magnetic nanoprobe/LC-MS/MS |
Mulder 2018 [52] | Ca2+ signaling and cytoskeleton organizing -related proteins (↑) | mTOR and MAPK signaling pathway (↑) | Bypass and downstream pathway activation | Afatinib (2nd) | PC9 treated with Afatinib | Phosphopeptide Enrichment LC-MS/MS |
Li 2018 [53] | upregulated proteins or ubiquitylated proteins (↑) | Autophagy (↑) | Miscellaneous | Gefitinib (1st) | PC9 vs. PC9/GR | LC-MS/MS, SILAC labeling |
Ku 2018 [54] | phosphorylation of ERK and WNK1 (↑) EGFR phosphorylation (↓) | ERK signaling (↑) | Bypass and downstream pathway activation | Osimertinib (3rd) | PC9 vs. PC9/OsiR | Proteome profiler array |
Yi 2018 [55] | ANXA2 (↑) | EMT (↑) | Histological transformation | Gefitinib (1st) | HCC827 cultured with CAF vs. cultured with NF | 2DE-MALDI-TOF/TOF MS |
Jacobsen 2017 [56] | AXL, ITGAV, IGFR2, CRKL, mTOR, MID1, LOXL2 (↑) | PI3K-Akt-mTOR signaling pathway (↑) | Bypass and downstream pathway activation | Erlotinib (1st) | PC9 vs. PC9/ER | LC-MS/MS, SILAC labeling |
Wilson 2014 [57] | FAK and proteins associated with Src/FAK signaling (EPHB1, ACK-1, CASL, BCAR3, VCL, ABL1) (↑) | Src/FAK pathway (↑) | Bypass and downstream pathway activation | Erlotinib (1st) | HCC827 parental vs. mesenchymal | Immunoaffinity enrichment of pTry phosphopeptides/LC-MS |
Yoshida 2014 [58] | phosphopeptides corresponding to MET, AXL, and IRS2 and SFK (↑) | SFK signaling (↑) | Bypass and downstream pathway activation | Gefitinib (1st) | PC9 vs. PC9/GR | immunoaffinity purification of tyrosine-phosphorylated peptides LC/MS-MS |
Byers 2013 [59] | AXL (↑) E-cadherin (↓) | EMT (↑) | Histological transformation | Erlotinib (1st) | NSCLC Mesenchymal cells vs. epithelial cells | RPPA |
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Moonmuang, S.; Tantraworasin, A.; Orrapin, S.; Udomruk, S.; Chewaskulyong, B.; Pruksakorn, D.; Chaiyawat, P. The Role of Proteomics and Phosphoproteomics in the Discovery of Therapeutic Targets and Biomarkers in Acquired EGFR-TKI-Resistant Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2023, 24, 4827. https://doi.org/10.3390/ijms24054827
Moonmuang S, Tantraworasin A, Orrapin S, Udomruk S, Chewaskulyong B, Pruksakorn D, Chaiyawat P. The Role of Proteomics and Phosphoproteomics in the Discovery of Therapeutic Targets and Biomarkers in Acquired EGFR-TKI-Resistant Non-Small Cell Lung Cancer. International Journal of Molecular Sciences. 2023; 24(5):4827. https://doi.org/10.3390/ijms24054827
Chicago/Turabian StyleMoonmuang, Sutpirat, Apichat Tantraworasin, Santhasiri Orrapin, Sasimol Udomruk, Busyamas Chewaskulyong, Dumnoensun Pruksakorn, and Parunya Chaiyawat. 2023. "The Role of Proteomics and Phosphoproteomics in the Discovery of Therapeutic Targets and Biomarkers in Acquired EGFR-TKI-Resistant Non-Small Cell Lung Cancer" International Journal of Molecular Sciences 24, no. 5: 4827. https://doi.org/10.3390/ijms24054827