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Peptide G-Protein-Coupled Receptors and ErbB Receptor Tyrosine Kinases in Cancer
Terry W Moody1, Irene Ramos-Alvarez1, Robert T Jensen1
1Center for Cancer Training, NCI, and Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892, USA.
Abstract:
The ErbB RTKs (EGFR, HER2, HER3, and HER4) have been well-studied in cancer. EGFR, HER2, and HER3 stimulate cancer proliferation, principally by activating the phosphatidylinositol-3-kinase and extracellular signal-regulated kinase (ERK) pathways, resulting in increased cancer cell survival and proliferation. Cancer cells have high densities of the EGFR, HER2, and HER3 causing phosphorylation of tyrosine amino acids on protein substrates and tyrosine amino acids near the C-terminal of the RTKs. After transforming growth factor (TGF) α binds to the EGFR, homodimers or EGFR heterodimers form. HER2 forms heterodimers with the EGFR, HER3, and HER4. The EGFR, HER2, and HER3 are overexpressed in lung cancer patient tumors, and monoclonal antibodies (mAbs), such as Herceptin against HER2, are used to treat breast cancer patients. Patients with EGFR mutations are treated with tyrosine kinase inhibitors, such as gefitinib or osimertinib. Peptide GPCRs, such as NTSR1, are present in many cancers, and neurotensin (NTS) stimulates the growth of cancer cells. Lung cancer proliferation is impaired by SR48692, an NTSR1 antagonist. SR48692 is synergistic with gefitinib at inhibiting lung cancer growth. Adding NTS to lung cancer cells increases the shedding of TGFα, which activates the EGFR, or neuregulin-1, which activates HER3. The transactivation process is impaired by SRC, matrix metalloprotease, and reactive oxygen species inhibitors. While the transactivation process is complicated, it is fast and occurs within minutes after adding NTS to cancer cells. This review emphasizes the use of tyrosine kinase inhibitors and SR48692 to impair transactivation and cancer growth.
Insights
Targeting ErbB receptor tyrosine kinases (RTKs) and neurotensin receptor 1 (NTSR1) with inhibitors like gefitinib and SR48692 can block cancer cell proliferation. These drugs impair transactivation pathways crucial for tumor growth, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- ErbB receptor tyrosine kinases (RTKs), including EGFR, HER2, HER3, and HER4, are key drivers of cancer proliferation via phosphatidylinositol-3-kinase and ERK pathways.
- Overexpression of EGFR, HER2, and HER3 is common in lung and breast cancers, leading to increased cell survival and proliferation.
- Targeted therapies like monoclonal antibodies (e.g., Herceptin) and tyrosine kinase inhibitors (e.g., gefitinib, osimertinib) are established treatments for cancers with specific ErbB alterations.
Purpose of the Study:
- To review the role of ErbB RTKs and peptide GPCRs, specifically NTSR1, in cancer proliferation.
- To highlight the therapeutic potential of combining tyrosine kinase inhibitors with NTSR1 antagonists.
- To discuss the mechanism of transactivation and its inhibition in cancer growth.
Main Methods:
- Review of existing literature on ErbB RTKs, NTSR1, and their signaling pathways in cancer.
- Analysis of the synergistic effects of tyrosine kinase inhibitors and NTSR1 antagonists on cancer cell proliferation.
- Examination of the transactivation process involving growth factors and receptor dimerization.
Main Results:
- Neurotensin (NTS) stimulates cancer cell growth by activating NTSR1 and promoting the shedding of TGFα or neuregulin-1, which in turn activate EGFR and HER3.
- The NTSR1 antagonist SR48692 synergizes with the EGFR inhibitor gefitinib to impede lung cancer growth.
- Transactivation, although complex and rapid, can be inhibited by targeting key mediators like SRC, matrix metalloproteases, and reactive oxygen species.
Conclusions:
- Targeting both ErbB RTKs and NTSR1 pathways offers a promising strategy for enhancing cancer treatment efficacy.
- Inhibiting receptor transactivation through combined therapies holds potential for overcoming treatment resistance and improving patient outcomes.
- Further research into the intricate mechanisms of transactivation can uncover novel therapeutic targets for various cancers.
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