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Target: KIT


Research on the Target KIT

1. Target Summary:

The KIT gene encodes a receptor tyrosine kinase (RTK) known as c-KIT, which plays a crucial role in various biological processes, including cell proliferation, survival, and differentiation. It is primarily activated by its ligand, stem cell factor (SCF). Dysregulation of c-KIT signaling is implicated in several cancers, particularly gastrointestinal stromal tumors (GISTs), melanoma, and mastocytosis. Mutations in the KIT gene can lead to constitutive activation of the receptor, promoting tumorigenesis.

2. Mechanism:

c-KIT is a type III receptor tyrosine kinase that, upon binding to SCF, undergoes dimerization and autophosphorylation, activating downstream signaling pathways. The activation of c-KIT leads to the recruitment of various signaling proteins, including those involved in the MAPK and PI3K/AKT pathways, which regulate cell proliferation, survival, and migration (Sheikh et al., 2022; PMID: 35490363).
The c-KIT receptor is composed of an extracellular domain that binds SCF, a single transmembrane domain, and an intracellular tyrosine kinase domain. Upon ligand binding, the receptor dimerizes, leading to the phosphorylation of tyrosine residues in the activation loop and juxtamembrane domain, which further propagates the signaling cascade (Zhou et al., 2024; PMID: 38414063).

3. Approved Drugs:

Several tyrosine kinase inhibitors (TKIs) target c-KIT, including:
  • Imatinib (Gleevec): Approved for GISTs and chronic myeloid leukemia (CML).
  • Sunitinib (Sutent): Approved for GISTs and renal cell carcinoma.
  • Dasatinib (Sprycel): Approved for CML and Ph+ ALL.
  • Ripretinib (Qinlock): Approved for GISTs after prior treatment with other TKIs.

4. Hypotheses:

  1. Targeting c-KIT may improve treatment outcomes: In cancers where c-KIT is a driver mutation, targeting this receptor with TKIs can lead to significant clinical benefits (Demetri, 2001; PMID: 11740803).
  2. Resistance mechanisms: Secondary mutations in the c-KIT gene may lead to resistance against TKIs, necessitating the development of next-generation inhibitors (Zhou et al., 2024; PMID: 38414063).
  3. Combination therapies: Combining c-KIT inhibitors with immune checkpoint inhibitors may enhance therapeutic efficacy in KIT-mutant melanoma (Hirai et al., 2021; PMID: 34889232).

5. Validation:

Clinical studies have demonstrated the efficacy of c-KIT inhibitors in improving survival rates in patients with c-KIT-positive tumors. For instance, imatinib has shown a 70-80% increase in survival after two years compared to treatments without c-KIT targeting (Abbaspour Babaei et al., 2016; PMID: 27536065). However, resistance mechanisms, such as secondary mutations in the c-KIT gene, have been identified, highlighting the need for ongoing research into novel therapeutic strategies (Zhou et al., 2024; PMID: 38414063).

6. Clinical Trials:

Recent clinical trials have focused on the efficacy and safety of c-KIT inhibitors:
  • Imatinib in GISTs: A phase II study showed a 69% partial response rate in patients with advanced GIST (Nishida et al., 2008; PMID: 18553235).
  • Combination of Imatinib and Pembrolizumab: A phase I/II trial is evaluating the safety and efficacy of this combination in patients with KIT-mutant melanoma (Hirai et al., 2021; PMID: 34889232).
  • Dovitinib in Glioblastoma: A phase I trial assessed the safety of dovitinib, a multi-tyrosine kinase inhibitor, in recurrent glioblastoma (Schafer et al., 2016; PMID: 27100354).

7. Involved Pathways:

c-KIT signaling is involved in several key pathways:
  • MAPK Pathway: Regulates cell proliferation and differentiation.
  • PI3K/AKT Pathway: Promotes cell survival and growth.
  • JAK/STAT Pathway: Involved in hematopoiesis and immune responses.

8. Associated Genes:

  • SCF (Stem Cell Factor): The ligand for c-KIT.
  • PDGFRA (Platelet-Derived Growth Factor Receptor Alpha): Often co-mutated with c-KIT in GISTs.
  • BCR-ABL: An oncogenic fusion protein targeted by imatinib.

9. Target Expression:

c-KIT is expressed in various tissues, including:
  • Hematopoietic stem cells
  • Melanocytes
  • Interstitial cells of Cajal in the gastrointestinal tract
  • Mast cells

10. Additional Context:

c-KIT mutations are particularly prevalent in GISTs, where they are found in approximately 80-90% of cases. The presence of these mutations is a critical factor in determining the efficacy of c-KIT-targeted therapies. Understanding the specific mutations and their effects on receptor function is essential for optimizing treatment strategies (Zhou et al., 2024; PMID: 38414063).

11. References:

  • Sheikh, E., Tran, T., & Vranic, S. (2022). Role and significance of c-KIT receptor tyrosine kinase in cancer: A review. Bosnian Journal of Basic Medical Sciences. PMC9519160
  • Demetri, G. D. (2001). Targeting c-kit mutations in solid tumors: scientific rationale and novel therapeutic options. Seminars in Oncology. PMID: 11740803
  • Zhou, S., Abdihamid, O., & Tan, F. (2024). KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST. Cell Communication and Signaling. PMID: 38414063
  • Hirai, I., Tanese, K., & Fukuda, K. (2021). Imatinib mesylate in combination with pembrolizumab in patients with advanced KIT-mutant melanoma following progression on standard therapy: A phase I/II trial and study protocol. Medicine. PMID: 34889232
  • Nishida, T., Shirao, K., & Sawaki, A. (2008). Efficacy and safety profile of imatinib mesylate in Japanese patients with advanced gastrointestinal stromal tumors: a phase II study. International Journal of Clinical Oncology. PMID: 18553235
  • Schafer, N., Gielen, G. H., & Kebir, S. (2016). Phase I trial of dovitinib (TKI258) in recurrent glioblastoma. Journal of Cancer Research and Clinical Oncology. PMID: 27100354