Targeting Signaling Pathways in Cancer

• The slides discuss targeting signaling pathways for precision cancer medicine, presented by Dr. Benoit Bilanges from the UCL Cancer Institute, Faculty of Medical Sciences, with contact information provided as [email protected].

Learning Outcomes

• Understand instances of deregulated signal transduction in cancer.
• Recognize, given their complexity, the role of signal transduction in cancer.
• Identify ways that deregulated signal transduction in cancer can be therapeutically targeted.
• Recognize the issues and challenges of targeted therapies, such as resistance, in cancer treatment.

Lecture Layout

• The lecture is divided into 3 parts
• Part 1: Signal transduction and key signaling pathways in cancer
• Part 2: Deregulated signalling in cancer & targeted therapies - Examples
• Part 3: Challenges & issues of targeted therapies

Hallmarks of Cancer

• Sustaining proliferative signaling is a feature of Cancer
• Evading growth suppressors is a feature of Cancer
• Negative regulators/growth suppressors maintain cellular homeostasis via inhibiting excessive cell division
• Cancer's negative regulators are often deleted/inactivated to proliferate rapidly
• Cancer cells exhibit deregulated signalling pathways driving processes, contributing to uncontrolled cell division

Cancer Heterogeneity

• It is a heterogeneous disease having different subpopulations within the same tumor or across different tumors which have distinct genetic mutations and protein expressions
• Complexity exists even within same cancer type.

Breast Cancer Example

• Example provides insights into heterogeneity
• Sequencing and profiling reveals multiple subgroups and molecular signatures of breast cancer
• Differences in genes are driven by dysregulation of signaling pathways, affecting cell behavior and resistance

Signal Transduction

• Extracellular signals are captured by cell surface receptors, translated into intracellular ones, like second messengers
• Phosphorylation cascades can be triggered through receptor tyrosine kinases (RTKs).
• A signal is transmitted through cells, reaching the nucleus inducing transcriptional responses such as proliferation, growth, survival.

Signalling Pathways

• Operational in normal cells under tight control due to feedback loops and negative regulators
• Regulatory process prevents continuous activation maintaining cellular homeostasis. Dysregulation, inactivation, or deletion of negative regulators in cancer lead to continuous signaling.

Cell Signalling

• It isn't linear, but is interconnected where pathways can cross-talk
• Increased signaling complexity is a feature of cancer cells

Signalling Network

• Normally a linear process, that instead has elements and characteristics of the cell signalling network
• Interconnection of networks mean there is cross-talk
• Cellular response and behavior causes an increase in complexity particularly the cancer cells

Cell Signalling Complexity

• Involves circuits and pathways
• Circuits regulate various processes such as viability, differentiation, proliferation and motility
• The circuits refer to inter-connected network signaling pathways.

Cell Signalling Deregulation

• Deregulation and uncontrolled cell proliferation and survival happens because signalling pathways in cancer cells are no longer held under tight control
• Allows growth, survival, and migration
• Most often external signals that enter cancer cells deregulated and escape control
• Some signalling pathways can be targeted

Cancer Cell Signalling

• Signal transduction pathways can exhibit oncogene overactivity or loss of tumor suppressors.
• Alterations affect cell behavior, growth, proliferation, resistance
• Common Signaling Pathways are RTK/RAS, Nrf2, PI3K , TGFP pathways + more

Examples of dysregulated signalling

• PI3K/AKT/mTOR: role in cellular survival and growth
• RAS/RAF/MEK/ERK (MAPK) Pathway is Involved in proliferation
• Wnt/ẞ- catenin Pathway: is involved in the regulation of stem sells and tumorigenesis
• Notch Signalling Pathway is involved in differentiation and apoptosis + more pathways

Aberrant Kinases

• Mutations in RTK/RAS pathway can be found at receptor level
• The signal from this causes changes in cell survival translation and proliferation

Disrupted RAS-RAF Pathway

• Mutation that activates the pathway independent of extracellular factors as part oncogenic BRAF signalling
• This excessive cell proliferation and survival occurs when there is an increased and normal Normal cell proliferation
• Excessive pathway also removes reliance or normal regulatory signals

Disrupted AKT-mTOR Pathway

• Growth factor stimulation activates receptor tyrosine, which then activates P13-kinase (PI3K) to produce phosphatidylinositol triphosphate at the membrane
• Activated AKT triggers which phosphorylates downstream targets

p53 Pathway and Cancer

• It is a transcription factor that functions as the genome "guardian" that regulates functions such as cell division, growth, and apoptosis
• Cancer cell mutation is more sensitive to cellular proliferation

Dysregulation Mechanisms in Cancers

• Genetic mutations to oncogenes and negative regulators contribute to dysregulation
• Epigenetic modification prevents cell proliferation

Drug Targeting

• Involves small molecule inhibitors (enzymes) or allosteric inhibition
• Use of proliferation growth survival pathways as target for cancer therapy

Targeted Therapies

• Use of small-molecule drugs target intended protein where entering happens easy
• Use monoclonal antibodies by specifically targeting cancer cells

Part 2: Deregulated Signalling In Cancer & targeted therapies

EGF-Receptor Targeting

• growth factor and receptor targets.
• intracellular transduction level, examples ATM kinase, BRCA
• cellular proliferation targets

Inhibiting EGF Receptors

• It occurs using tyrosine kinase receptors present in the plasma membrane and involves the use of antibody and kinase inhibition

BCR-ABL Targeting

• Involves using growth factor, growth factor receptor, and intracellular transduction

Disrupted BCR-ABL Fusion

• Imatinib was one of the first small molecule kinase inhibitors and was specifically designed to target BCR-ABL and Block kinase activity

BRAF Targeting

• The growth factor has targets such as epidermal growth factor, growth factory receptor and intercellular structures
• The proteins that take part in activation are transcription factors, DNA RNA AND MRNA
• The final elements and results are used in a variety of processes

B-Raf Kinase and Melanoma

• V600E- is targeted using vermurafenib which prevents tumor growth by limiting signaling

PI3K Targeting

• Involves the various elements that are found cell functions
• The process inhibits or manages a variety of targets but are most commonly applied to PI3K targets.

PI3K and Rare Diseases

• They exist due to mutations in key areas and are cancer predisposed later in life
• Also occur with other autoimmune functions and aspects
• Genetic disposition can increase or decrease the chances of specific cancer

Targeting PTEN and P110a

• Oncogenic receptor is most affected by Ras: this can then relay the molecules
• Very frequent mutated activated in cancer
• AKT/PKB activated as result for cell survival and growth
• Specific to lung, colorectal and breast
• PTEN also involved which lead to somantic and sporadic cancers
• Wildfire caused by 'littered' tumour suppressor

Cancer Cell Targeting

• Some signal transduction pathways are overactive in cancer, often as a consequence of oncogenic mutation/loss of tumour suppressors. Red indicates proteins or genes that are mutated
• Some Signaling Pathways - Wnt | Nrf2 | Mycc | HIPPO

Pt 3: Challenges & issues of targeted therapies

• Challenge is that some of key nodes in cancer signalling - that aren't considered druggable because to the difficulty and functions with it

Intrinsic resistance

• PTEN and Cylin loss + more

Cancer cell resistance

• It refers to when the cells are able to develop properties to reduce inhibition despite treatment - that are the result of heterogeneity

Cancer Cell Developement and therapeutic Resistance causes multiple changes:

• This can happen where mutations binding is preventing + feedback of looping + other new finds

New Avenues for resistance

• This is the cause of cell survivial
• In general multiple routes create more problems than a specific target

Increased Survival and Mutation

• Some of these aspects result in increased cell activity - which will damage patients at a more rapid cause of cell destruction

Therapeutic resistance

• There is usually a target change and alterations on cell signaling and genes

Issues with targets

• Side effects occur due to the effect on cells and tissues targeted

Targeted Toxicitiy

• inhibitors must be selected due to different classes of Kinase
• pharmeuciuqla companies try broad range to prevent certain pathways

Targeted Side Effects

• Many inhibitors lack strong specificity and can inhibit non-intended targets
• These lead to several problems in the long-run

Overcoming Toxicity

• Selective inhibitors must be targeted at appropriate tissue
• The same should also be used for reducing growth

Overcoming issues

• Can use smaller levels targeted in other to avoid increasing side effects
• genetic profiles and functions should assist in targeted therapies
• This can lead to combining treatments and the best use of combination analysis and function

Clinical Issues

• Most of the solutions can revolve around selection and focus
• Genotypes prevent genetic and clinical phenotypes for target to be used at will