Kinase inhibitors in cancer treatment research presentation for medical students.
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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.
3.
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):
8.
9. Kinase inhibitors can be
categorized based on
their mechanism of action
into two main groups:
Small molecule inhibitors
and Monoclonal
antibodies.
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
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
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.
