RTKs: Precision Cancer Therapy Targets

Receptor tyrosine kinases (RTKs) are pivotal in both normal cellular functions and cancer progression, activating critical signaling pathways. In cancer therapy, targeted treatments against specific RTKs have shown significant success, utilizing monoclonal antibodies and small molecule drugs. Examples include ALK inhibitors for non-small cell lung cancer and lymphomas, and inhibitors of AXL , c-Kit , c-Met , and others in various cancers. Research utilizing recombinant proteins from Sino Biological has elucidated binding specificities and validated novel therapeutic approaches, highlighting the importance of RTKs in personalized cancer therapies. The merger between Sino Biological and SignalChem Biotech (SCB) further enhances research capabilities by offering a comprehensive range of RTK domains for both monoclonal antibody and small molecule drug development, advancing the field of precision cancer therapies.

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Physiological and Pathological Roles

RTKs are a diverse group of over 60 transmembrane protein subtypes that act as receptors for cytokines, growth factors, hormones, and other signaling molecules (1,2). They include families such as EGFR , PDGFR , MCSFR , IGF1R , INSR , NGFR , FGFR , VEGFR , and HGFR (3-5). RTKs play crucial roles in normal cellular functions by activating signaling pathways like MAPK, PI3K/AKT, and JAK/STAT upon ligand binding (5). These pathways regulate cellular proliferation, survival, migration, and angiogenesis. In cancer, RTK mutations, overexpression, or aberrant activation may lead to uncontrolled cell division, resistance to apoptosis, and increased metastatic potential, contributing to various malignancies such as breast, lung, and colorectal cancers (2,5).

Bench to Bedside

RTKs are crucial in cancer therapy due to their role in cell signaling and tumorigenesis1. Therapeutic agents targeting RTKs include monoclonal antibodies and small molecule drugs (1,6). Monoclonal antibodies block ligand binding by targeting the extracellular domain of RTKs, while small molecule drugs inhibit kinase activity by targeting the intracellular kinase domain (3,7). Targeted treatments against specific RTKs have shown significant success in various cancers. For example, ALK inhibitors like crizotinib have been approved by the U.S. Food and Drug Administration (FDA) to treat ALK-positive non-small cell lung cancer (NSCLC) and lymphomas (8,9). AXL inhibitors are approved for thyroid cancer, renal cell carcinoma, and acute myeloid leukemia (AML). Inhibitors of c-Kit such as imatinib are effective in gastrointestinal stromal tumors and AML. Currently market-approved c-Met inhibitors like capmatinib can be used to target metastatic non-small cell lung cancer. DDR inhibitors such as nilotinib are available for the treatment of chronic granulocytic leukemia, and clinical studies are explored in breast and ovarian cancers. EPH receptor inhibitors disrupt signaling in lung, colon, and breast cancers. FLT3 inhibitors, including midostaurin, significantly improve outcomes in FLT3-mutant AM L (10). HER family inhibitors, such as trastuzumab and erlotinib, revolutionize treatment for HER2-positive breast cancer (11). These advancements from bench to bedside highlight the critical role of RTKs in developing personalized cancer therapies.

Application in Research

Sino Biological’s products are frequently cited in well-reputed journals. Ning et al. conducted BLI kinetic analysis using recombinant AXL (Cat#: 10279-H08H , Sino Biological) in the presence of VP1u. Their findings confirmed that AXL binds to VP1u in vitro (12). In a separate study, Upadhyaya et al. developed a novel bicyclic binder molecule aimed at modulating immune costimulatory receptors for cancer therapy. They validated the binding of their molecule with recombinant EphA2 (Cat#: 50586-M08H , Sino Biological) using SPR analysis (13). Chauvin and colleagues determined the binding specificity of their monoclonal and bispecific antibodies to ALK2 (Cat#: 10227?H08B , Sino Biological) and ALK3 (Cat#: 10446?H08H , Sino Biological) using an ELISA assay (14). Perez et al. utilized recombinant FLT3 protein (Sino Biological) in a high-throughput kinase assay with a focused peptide library. They validated multiple phosphorylation events, including KIT, PDGFRB, ALK, BTK, SRC, and LYN (15).

A Merger of Extracellular Expertise and Intracellular Innovation

Sino Biological offers a broad spectrum of antigen domains from essential RTKs, perfect for advancing immunotherapies and cell therapies. Meanwhile, SignalChem Bio specializes in intracellular kinase domains, ideal for precision small molecule drug targeting. The recent merger marks a major step forward, bringing together these resources to create the most comprehensive collection of RTK domains to date. This extensive range propels research and development in therapeutic agents, driving progress in both biologics and small molecule drug development.

References

1. Trenker, R. & Jura, N. Receptor tyrosine kinase activation: From the ligand perspective. Current Opinion in Cell Biology vol. 63 174–185 Preprint at https://doi.org/10.1016/j.ceb.2020.01.016 (2020).

2. Saraon, P. et al. Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches. Oncogene vol. 40 4079–4093 Preprint at https://doi.org/10.1038/s41388-021-01841-2 (2021).

3. Zhong, L. et al. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduction and Targeted Therapy vol. 6 Preprint at https://doi.org/10.1038/s41392-021-00572-w (2021).

4. Lima, L. M., de Castro Barbosa, M. L., do Amaral, D. N. & Barreiro, E. J. Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR. in Topics in Medicinal Chemistry vol. 36 155–201 (Springer Science and Business Media Deutschland GmbH, 2021).

5. Esteban-Villarrubia, J. et al. Tyrosine kinase receptors in oncology. Int J Mol Sci 21, 1–48 (2020).

6. Rendell, A. et al. Targeting Tyrosine Kinases in Ovarian Cancer: Small Molecule Inhibitor and Monoclonal Antibody, Where Are We Now? Biomedicines vol. 10 Preprint at https://doi.org/10.3390/biomedicines10092113 (2022).

7. Linguanti, F., Abenavoli, E. M., Calabretta, R., Berti, V. & Lopci, E. ImmunoPET Targeting Receptor Tyrosine Kinase: Clinical Applications. Cancers vol. 15 Preprint at https://doi.org/10.3390/cancers15245886 (2023).

8. Takiar, R. & Phillips, T. J. Durable responses with ALK inhibitors for primary refractory anaplastic lymphoma Kinase-positive large B-cell lymphoma. Blood Adv 7, 2912–2916 (2023).

9. Shaw, A. T. et al. First-Line Lorlatinib or Crizotinib in Advanced ALK -Positive Lung Cancer. New England Journal of Medicine 383, 2018–2029 (2020).

10. O?ate, G. et al. Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort. Blood Cancer J 13, 69 (2023).

11. Drago, J. Z., Ferraro, E., Abuhadra, N. & Modi, S. Beyond HER2: Targeting the ErbB receptor family in breast cancer. Cancer Treat Rev 109, 102436 (2022).

12. Ning, K. et al. Identification of AXL as a co-receptor for human parvovirus B19 infection of human erythroid progenitors. Sci Adv 9, (2023).

13. Upadhyaya, P. et al. Anticancer immunity induced by a synthetic tumor-targeted CD137 agonist. J Immunother Cancer 9, e001762 (2021).

14. Chauvin, M. et al. Anti-Müllerian hormone concentration regulates activin receptor-like kinase-2/3 expression levels with opposing effects on ovarian cancer cell survival. Int J Oncol 59, 43 (2021).

15. Perez, M., Blankenhorn, J., Murray, K. J. & Parker, L. L. High-throughput Identification of FLT3 Wild-type and Mutant Kinase Substrate Preferences and Application to Design of Sensitive In Vitro Kinase Assay Substrates. Molecular & Cellular Proteomics 18, 477–489 (2019).