Background
Structure and classification of RTKs
Breast cancer stem cells and drug resistance
Role of receptor tyrosine kinase (RTK) signaling in breast cancer progression
EGFR: A key regulator of cancer stem cell phenotype and metastasis in inflammatory breast cancer
VEGFRs: Master nodes in VEGF-regulated metastasis, tumor angiogenesis and lymphangiogenesis
PDGFR: promising role in tumor-stroma interaction in breast carcinoma
FGFR: aberrantly expressed in breast cancer and implications in targeted therapy
Role of miRNAs and lncRNAs in regulation of RTK signaling
Serial No. | Molecule | miRNA/lncRNA | Target RTK pathway | Pathological function |
---|---|---|---|---|
1 | MiR-26a/b | miRNA | EGFR (ErbB2) | Regulates expression of ErbB2; competes with HuR for binding to its 3’UTR in tamoxifen-resistant ER+ breast cancer [95] |
2 | MiR-34a | miRNA | EGFR (ErbB2) | Downregulates expression of ErbB2 [96] |
3 | MiR-155 | miRNA | EGFR (ErbB2) | Downregulates HDAC2, a transcriptional activator of ErbB2; binds directly to a regulatory sequence over the coding region of ErbB2 [97] |
4 | MiR-24 | miRNA | EGFR | Regulates levels of phospho-EGFR by targeting phosphatases, PTPN9 and PTPRF [98] |
5 | MiR206 | miRNA | EGFR, MET | Downregulates EGFR and c-MET [99] |
6 | H19/miR675 | lncRNA/daughter miRNA | EGFR, MET | Stabilizes EGFR and c-MET by targeting c-Cbl and Cbl-b [100] |
7 | CYTOR | lncRNA | EGFR | Regulates expression of EGFR pathway specific genes [101] |
8 | BCAR4 | lncRNA | ErbB2/3 | BCAR4 enhances ErbB2/3 activity in tamoxifen-resistant breast cancer [102] |
Role of RTK signaling in drug resistance
Receptor tyrosine kinase (RTK)-targeted cancer therapeutics
Clinical studies of RTK-targeted therapeutics in breast cancer | ||||
---|---|---|---|---|
Molecule | Target | Outcome | Ref. | |
Gefitinib +Epirubicin and Cyclophosphamide | EGFR | No significance | [146] | |
Cetuximab + Carboplatin | EGFR | Overall response rate: 6% (Carb), 16% (Carb + cetux), TTP - 2.1 month | [148] | |
Cetuximab + Cisplatin | EGFR | Overall response rate: 10% (cis), 20% (cis + cetux) P=0.032 | [149] | |
Cetuximab + Ixabepilone | EGFR | No significance | [150] | |
Cetuximab + Irinotecan | EGFR | Overall response rate: 11% | [151] | |
Panitumumab + Epirubicin, Fluorouracil and Cyclophosphamide (EFC) + Docetaxal | EGFR | Pathological complete response: 47% | [152] | |
Cetuximab + Docetaxal | EGFR | Pathological complete response: 24% | [153] | |
Panitumumab+Paclitaxal and Carboplatin | EGFR | Overall response rate: 46% | [154] | |
Erlotinib + Bendamustine | EGFR | Cause excessive toxicity with severe, prolonged lymphopenia | [155] | |
Paclitaxal + Bevacizumab | VEGFR | Higher progression free survival | [156] | |
Bevacizumab + Capacitabine | VEGFR | Higher progression free survival | [157] | |
Sunitinib + Docetaxal | VEGFR, PDGFR | No significant difference in progression free survival | [158] | |
Currently investigated clinical trials of targeting RTK in breast cancer | ||||
Molecule | Type | Target | Phase of study | Mechanism |
Trastuzumab | Humanized MAb | HER2 | In clinical use | Inhibits HFR2 and HER3 dimerization, induces ADCC [159] |
Cetuximab | ChimaricMAb | EGFR | Phase I, II | |
Panitumumab | Humanized MAb | EGFR | Phase II | |
Nimotuzumab | Humanized MAb | EGFR | Phase I | Induces NK cell mediated ADCC [162] |
Necitumumab | Humanized MAb | EGFR | Phase II | Inhibits downstream targets in EGFR pathway, induces ADCC [163] |
Gefitinib | Reversible TKI | EGFR | Phase I, II | Reverses TAM resistance by up-regulating the ERα [164] |
Erlotinib | Reversible TKI | EGFR | Phase I, II | Suppresses CDK2 activity [165] |
Lapatinib | Reversible TKI | EGFR, HER2 | In clinical use | Used as an alternate therapy in trastuzumab resistant HER2 positive breast cancer [139] |
Afatinib | Irreversible TKI | EGFR, HER2 | Phase II | Inhibits EGFR and HER2 signalling irreversibly [166] |
Varlitinib | Reversible TKI | EGFR, HER2, ErbB4 | Phase II | Inhbits HER/MAPK signalling in TNBC [167] |
Dacomitinib | Irreversible TKI | EGFR, HER2, ErbB4 | Phase 1, Solid tumors | Inhibits HER2, EGFR, HER4, Akt and ERK phosphorylation and show high antitumor effect in trastuzumab and lapatinib resistant HER2 overexpressing breast cancer [168] |
Sapitinib | Reversible TKI | EGFR, HER2, ErbB3 | Phase 1, Solid tumors | Showed higher inhibitory potential in tamoxifen resistant breast cancer [169] |
Vandetanib | TKI | EGFR, VEGFR2-3, RET | Phase I, II | Targets angiogenesis by inhibiting VEGFR2 and 3 signalling along with EGFR pathway [170] |
Neratinib | Irreversible TKI | EGFR, HER2, ErbB4 | Phase I, II, III | Irreversibly blocks EGFR and HER2 pathway [171] |
BMS-690514 | Irreversible TKI | EGFR, HER2, ErbB4, VEGFR1-3 | Phase 1, Solid tumors | Irreversibly blocks EGFR and HER2 pathway leading to inhibition of their downstream signaling pathways [172] |
AEE788 | Reversible TKI | EGFR, ErbB2, VEGFR | Phase I | Targets angiogenesis by inhibiting VEGFR2 and 3 signalling along with EGFR pathway [173] |
Lucitanib | TKI | FGFR 1-2, VEGFR 1-3, PDGFRα/β | Phase II | Show anti-angiogenic and anti-tumoral activity by targeting FGFR and VEGFR [174] |