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Kinase inhibitors in cancer treatment.pptx
- 2. Page 02 Objectives Mechanism of action of kinase inhibitors, exploring how they disrupt aberrant kinase activity and subsequently hinder the growth and survival signals in cancer cells. Types of kinase inhibitors commonly used in cancer treatment, such as small molecule inhibitors and monoclonal antibodies, and their respective modes of action. Clinical applications of kinase inhibitors across different cancer types including next-generation inhibitors, combination therapies, and the integration of kinase inhibitors with immunotherapy. We will discuss ongoing research efforts, such as overcoming resistance, identifying novel kinase targets, improving safety profiles, and predicting response through the use of biomarkers.
- 4. Kinases and their role in cellular signalling pathway • Kinases are a type of enzymes that play a crucial role in cellular signaling pathways. These pathways regulate various cellular processes, including cell growth, proliferation, differentiation, and survival. • Kinases function by transferring phosphate groups from adenosine triphosphate (ATP) to specific target proteins, a process known as phosphorylation. This phosphorylation event often leads to a change in protein function and initiates downstream signaling cascades. • Abnormal kinase activity can contribute to cancer development and progression.
- 5. Abnormal kinase activity can impact cellular processes and drive oncogenesis: Dysregulated Cell Growth and Proliferation Altered Signal Transduction Pathways Resistance to Cell Death Escape from Growth Suppression Enhanced Invasion and Metastasis Genetic Mutations and Chromosomal Rearrangements
- 6. Common kinases that have been implicated in cancer: •EGFR is a receptor tyrosine kinase involved in regulating cell growth and survival. Abnormal activation of EGFR, often through mutations or overexpression, has been found in several cancers, including non-small cell lung cancer (NSCLC), colorectal cancer, and head and neck squamous cell carcinoma (HNSCC). •EGFR-targeted therapies, such as gefitinib and erlotinib, have been developed to inhibit the abnormal signaling associated with EGFR mutations in NSCLC. Epidermal Growth Factor Receptor (EGFR): • HER2 is a member of the HER family of receptor tyrosine kinases. Amplification or overexpression of HER2 is frequently observed in breast cancer and is associated with a more aggressive phenotype. • Targeted therapies like trastuzumab and pertuzumab have been developed to specifically inhibit HER2 signaling and have shown efficacy in treating HER2-positive breast cancer. •Human Epidermal Growth Factor Receptor 2 (HER2):
- 7. Common kinases that have been implicated in cancer: • BRAF is a serine/threonine kinase involved in the MAPK signaling pathway, which regulates cell proliferation and survival. Mutations in the BRAF gene, such as the V600E mutation, are commonly found in melanoma and a subset of colorectal cancers. • Targeted therapies, such as vemurafenib and dabrafenib, have been developed to selectively inhibit the abnormal activity of mutant BRAF and have shown significant clinical benefit in patients with BRAF-mutant melanoma. •B-Raf Proto-Oncogene (BRAF):
- 9. Kinase inhibitors can be categorized based on their mechanism of action into two main groups: Small molecule inhibitors and Monoclonal antibodies.
- 10. Classification of small molecule kinase inhibitors
- 12. Small molecule kinase inhibitors are low molecular weight compounds that can enter cells and interact with the ATP-binding site of kinases. These inhibitors are typically administered orally and are able to penetrate cell membranes, allowing them to target intracellular kinases. Small Molecule Inhibitors: Mechanism of Action: Small molecule inhibitors competitively bind to the ATP-binding site of kinases, blocking ATP from binding and interfering with kinase activity. By inhibiting kinase activity, these inhibitors disrupt the downstream signaling pathways involved in cell growth, survival, and proliferation. Targeting Specific Kinases: Small molecule inhibitors can be designed to selectively target specific kinases implicated in cancer. They can be tailored to bind to the unique structural features of the targeted kinase's ATP-binding site, allowing for high specificity and selectivity. Examples: Examples of small molecule kinase inhibitors include imatinib (targeting BCR-ABL in chronic myeloid leukemia), erlotinib (targeting EGFR in non-small cell lung cancer), and vemurafenib (targeting mutant BRAF in melanoma).
- 13. • Monoclonal Antibodies: Monoclonal antibodies are large protein molecules designed to specifically bind to cell surface receptors or antigens on cancer cells. They are typically administered intravenously and are unable to penetrate cell membranes, meaning they primarily target extracellular kinases. • Mechanism of Action: Monoclonal antibodies bind to specific receptors or antigens on the surface of cancer cells, blocking ligand-receptor interactions or inducing immune-mediated responses against cancer cells. This can result in inhibition of downstream signaling pathways, antibody-dependent cellular cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). • Targeting Cell Surface Receptors: Monoclonal antibodies are particularly effective at targeting cell surface receptors involved in signaling pathways. By blocking the interaction between ligands and receptors, they prevent downstream signaling and inhibit tumor growth. • Examples: Examples of monoclonal antibody kinase inhibitors include trastuzumab (targeting HER2 in breast cancer), cetuximab (targeting EGFR in colorectal and head and neck cancers), and rituximab (targeting CD20 in non-Hodgkin lymphoma). • It's important to note that the choice between small molecule inhibitors and monoclonal antibodies depends on the specific target and the characteristics of the kinase being targeted. Small molecule inhibitors are effective for targeting intracellular kinases, while monoclonal antibodies are suitable for targeting extracellular or cell surface kinases. • Both small molecule inhibitors and monoclonal antibodies have made significant contributions to cancer treatment, providing targeted therapies that disrupt specific kinase activities involved in cancer cell growth and survival. They offer distinct mechanisms of action and can be used in combination or as standalone treatments, depending on the specific context of the disease and the targeted kinase. • Regenerate response Monoclonal inhibitors :
- 14. Small molecule inhibitors are effective for targeting intracellular kinases, while monoclonal antibodies are suitable for targeting extracellular or cell surface kinases.
- 15. Distinctions between Small Molecule Inhibitors and Monoclonal Antibodies • Small molecule inhibitors are small compounds that can penetrate cells and directly target intracellular kinases. They competitively bind to the ATP-binding site of the kinase, inhibiting its activity and disrupting downstream signaling pathways. • In contrast, monoclonal antibodies are large proteins that primarily target cell surface receptors. They bind to specific receptors or antigens, blocking ligand-receptor interactions and interfering with signaling cascades. • Small molecule inhibitors inhibit kinase activity, while monoclonal antibodies can induce receptor internalization or trigger immune-mediated responses. These distinctions in size, target specificity, and mechanism of action make small molecule inhibitors suitable for intracellular targets, while monoclonal antibodies are effective in blocking cell surface receptor-mediated signaling in cancer treatment
- 16. FDA-approved kinase inhibitors and their drug targets
- 17. D I V E R S E R A N G E O F C A N C E R S Kinase inhibitors like gefitinib and erlotinib have shown efficacy in NSCLC patients with activating EGFR mutations. 1. Non-small cell lung cancer (NSCLC): BRAF inhibitors such as vemurafenib and dabrafenib have shown significant benefits in patients with BRAF V600E or V600K mutations. 2. Melanoma : HER2-targeted kinase inhibitors like trastuzumab and lapatinib have improved outcomes in HER2- positive breast cancer patients. 3. Breast cancer: Imatinib and other tyrosine kinase inhibitors have revolutionized the treatment of CML, targeting the BCR-ABL fusion protein. Kinase inhibitors have demonstrated efficacy in a diverse range of cancers. Examples include: 4. Chronic myeloid leukemia (CML):
- 18. Molecular Profiling and Biomarker Testing: Molecular profiling and biomarker testing are vital in identifying patients who may benefit from kinase inhibitor therapy. By analyzing the genetic and molecular characteristics of tumors, specific alterations can be identified, guiding treatment decisions. Biomarkers, such as mutations, amplifications, or expression levels of specific kinases, help predict response to kinase inhibitors. Examples include testing for EGFR mutations in NSCLC to predict response to EGFR inhibitors and HER2 testing in breast cancer to guide HER2-targeted therapy.
- 19. Case study In a clinical trial for advanced melanoma patients with BRAF V600E mutation, treatment with the BRAF inhibitor vemurafenib resulted in significant tumor shrinkage and improved progression- free survival compared to chemotherapy. Case Study 1 Clinical trials evaluating the efficacy of the ALK inhibitor crizotinib in ALK-positive NSCLC patients showed substantial tumor response rates and prolonged progression-free survival. Case Study 2 HER2-targeted kinase inhibitors, such as trastuzumab, have demonstrated significant benefits in HER2-positive breast cancer patients, improving overall survival and reducing the risk of recurrence. Case Study 3
- 20. CHALLENGES ASSOCIATED WITH KINASE INHIBITOR THERAPY:
- 21. Resistance Off-Target Effects Toxicity Cost and Access Resistance One of the major challenges is the development of resistance to kinase inhibitors over time. Cancer cells can acquire genetic alterations or develop alternative signaling pathways, leading to diminished response to the inhibitor.
- 22. Resistance Off-Target Effects Toxicity Cost and Access Off-Target Effects •Kinase inhibitors may not be entirely specific to the intended target, resulting in off-target effects that can impact normal cellular functions and lead to adverse effects.
- 23. Resistance Off-Target Effects Toxicity Cost and Access Toxicity Some kinase inhibitors can cause side effects, ranging from mild to severe, affecting various organs and systems in the body.
- 24. Resistance Off-Target Effects Toxicity Cost and Access Cost and Access •The high cost of kinase inhibitors can limit access and affordability for some patients, creating disparities in receiving targeted therapy.
- 25. Overcoming Resistance to Kinase Inhibitors Combination Therapy Combining kinase inhibitors with other targeted agents, chemotherapy, or immunotherapy can improve treatment efficacy and overcome resistance mechanisms. Combinations can target multiple signaling pathways simultaneously and prevent the emergence of resistant clones. Second-Generation Inhibitors Developing second-generation inhibitors with improved potency, selectivity, and alternative mechanisms of action can overcome resistance mechanisms associated with first-generation inhibitors. Targeting Resistance Pathways: Identifying and targeting specific resistance mechanisms, such as secondary mutations or compensatory signaling pathways, can help overcome resistance to kinase inhibitors.
- 26. Side Effects and Management Strategies Monitoring and Early Detection: Regular monitoring of patients receiving kinase inhibitors helps detect and manage potential side effects promptly. Close monitoring of blood counts, liver function, cardiac function, and other relevant parameters is essential. Supportive Care: Symptom management and supportive care strategies, such as antiemetics, growth factor support, and supportive counseling, can help alleviate treatment- related side effects. Dose Optimization: Adjusting the dose of kinase inhibitors to find a balance between efficacy and tolerability can help manage side effects. Individualized dosing based on patient characteristics and response is crucial.
- 30. Conclusion
- 32. THANK YOU