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| Front | Explain how subversion of tyrosine kinasesignaling can promote tumorigenesis |
| Back | Subverting tyrosine kinase (TK) signaling is one of the most common ways a cell becomes cancerous. It essentially hotwires the cell's "grow" and "survive" circuits, providing the constant, rogue signals needed for tumor formation.This subversion provides two of the most critical hallmarks of cancer:Sustaining Proliferative Signaling: The "gas pedal" is permanently stuck down.Evading Cell Death: The "don't die" signal is permanently on.Here are the primary ways cancer cells subvert this pathway.1. π’ Autocrine Loop (The Cell Makes Its Own Signal)A normal cell only divides when it receives an external growth factor (a ligand). In this form of subversion, the cancer cell itself starts to produce and secrete its own growth factor.How it works: The cell secretes the ligand, which then binds to the tyrosine kinase receptors on its own surface. This creates a self-sustaining "autocrine loop" where the cell constantly tells itself to divide.Example: Some sarcomas and gliomas overproduce PDGF (Platelet-Derived Growth Factor), which binds to their own PDGF receptors.2. π Receptor Overexpression (Too Many "Receivers")This is a "quantitative" subversion. The cell doesn't change the receptor, it just makes a massive number of them, usually through gene amplification.How it works: The cell membrane becomes flooded with so many receptor tyrosine kinases (RTKs) that they are crowded together. This crowding can force them to pair up (dimerize) and activate spontaneously, even without a ligand. It makes the cell hyper-sensitive to even tiny amounts of growth factor.Example: HER2 (a member of the EGFR family) is amplified in ~20% of breast cancers. The massive number of HER2 receptors on the cell surface drives constant firing of pro-growth and pro-survival signals.3. π₯ Constitutive Activation (The "Stuck-On" Switch)This is a "qualitative" subversion where the receptor itself is broken by a mutation.How it works: A point mutation in the gene for the RTK changes the protein's shape. This can lock the kinase domain in a permanently "on" position. The receptor is now active 100% of the time, dimerization or not, ligand or not.Example: Certain EGFR mutations in non-small cell lung cancer lock the receptor's kinase domain in its active state, leading to constant signaling down the RAS and AKT pathways.4. 𧬠Chimeric Fusion Proteins (A "Monster" Kinase)This subversion results from a chromosomal translocation, where two different genes are broken and fused together, creating a new "monster" protein.How it works: The "head" of a random protein is fused to the "kinase engine" (the tyrosine kinase domain) of a proto-oncogene. This new fusion protein's structure causes it to be permanently "on" and active in the cytoplasm, firing signals 24/7.Example: The BCR-ABL "Philadelphia Chromosome" in Chronic Myeloid Leukemia (CML). The ABL tyrosine kinase is fused to the BCR protein, creating a new, hyperactive kinase that drives the massive overproduction of white blood cells.5. β‘ Downstream Pathway Activation (Bypassing the Receptor)Sometimes, the receptor is normal, but a key component downstream in the signaling cascade is hijacked.How it works: A mutation can get one of the "relay runners" (like RAS) stuck in its "on" state. When this happens, it doesn't matter if the receptor at the surface is on or off. The "Go" signal is now being generated from inside the cell and is unstoppable.Example: RAS mutations are incredibly common (e.g., in pancreatic and colon cancer). A mutated RAS is permanently "on" and continuously activates both the MAPK pathway (for proliferation) and the PI3K/AKT pathway (for survival).6. β Loss of "Off" Switches (Cutting the Brakes)Signaling pathways have "brakes" called phosphatases, which are enzymes that remove phosphates to turn the signal off.How it works: The cancer cell acquires a mutation that deletes or inactivates a key phosphatase (like PTEN, which is the brake for the PI3K/AKT pathway).Result: Even if the "on" signal from the RTK is normal and brief, the signal never gets turned off. The phosphorylation remains, and the pro-growth/pro-survival signal is sustained indefinitely. |
| Front | EGFR-RAS-MAPK pathway |
| Back | 1. Overview of the PathwayThe EGFR-RAS-MAPK pathway is a primary communication system that tells a cell when to grow, divide (proliferate), and survive. It's a "relay race" that carries a signal from the outside of the cell (a growth factor) to the nucleus (where the genes for division are).The key "runners" in this relay are:EGFR (Epidermal Growth Factor Receptor): A receptor tyrosine kinase (RTK) that acts as the "receiver" on the cell surface.RAS: A small "master switch" protein located just inside the cell membrane.MAPK Cascade (RAF-MEK-ERK): A chain of "domino" proteins (kinases) that amplify the signal.ERK: The final "anchor" in the relay, which enters the nucleus to activate the genes for cell division.2. How the Pathway Is RegulatedIn a normal cell, this pathway is kept under extremely tight control. It is "off" by default and only "on" for short bursts when needed.Activation (Turning "On"):Ligand Binding: The signal (e.g., Epidermal Growth Factor, EGF) binds to the outside of the EGFR receiver.Dimerization: This causes two EGFR receivers to pair up.Phosphorylation: The paired-up receivers "switch on" by adding phosphates to each other (autophosphorylation).RAS Activation: The "on" receptor recruits "helper" proteins that swap the GDP (off) on RAS for a GTP (on).Cascade: "On" RAS activates RAF, which activates MEK, which activates ERK.Gene Expression: ERK moves to the nucleus and turns on genes that tell the cell to divide.Inactivation (Turning "Off"):Phosphatases: These enzymes are the "brakes." They remove the phosphate groups from the receptors, shutting them down.GAPs (GTPase-Activating Proteins): These are "off-switch helpers" for RAS. They help RAS cut the GTP back to GDP, forcing it into the "off" state.Receptor Endocytosis: The cell "swallows" the activated receptor and destroys it in the lysosome (the cell's "garbage disposal") to terminate the signal.3. How Regulation Gets Subverted in CancerCancer hijacks this pathway by breaking the "off" switches or locking the "on" switches, resulting in a signal that is constitutive (permanently "on").Receptor Level (EGFR):Gene Amplification: The cell makes hundreds of copies of the HER2 (an EGFR-family) gene. This floods the cell surface with so many receptors they fire spontaneously, even without a signal.Point Mutations: In some lung cancers, a mutation in EGFR itself locks it in the "on" position, making it signal 24/7.Switch Level (RAS):Point Mutations: This is the most common subversion. A mutation in KRAS (e.g., G12C) changes its shape so that GAPs (the "off-switch helper") can no longer bind. RAS is now locked in the "on," GTP-bound state, permanently firing signals.Cascade Level (BRAF):Point Mutations: In melanoma, a mutation (e.g., BRAF V600E) locks the RAF protein (the first step after RAS) in a permanently "on" state. This bypasses the need for signals from both EGFR and RAS.4. How This Contributes to TumorigenesisA permanently "on" pathway directly provides the cell with several of the Hallmarks of Cancer:Sustained Proliferative Signaling: This is the most direct result. The constant ERK signal to the nucleus forces the cell to pass the G1/S checkpoint and divide over and over, ignoring all external "stop" signals. It no longer needs growth factors to grow.Evading Cell Death (Apoptosis): Oncogenic RAS also activates a parallel "survival" pathway (the PI3K/AKT pathway). This pathway tells the cell "don't die," blocking its internal self-destruct program and making it resistant to stress.Deregulating Cellular Metabolism: The PI3K/AKT branch also "rewires" the cell's metabolism, telling it to consume huge amounts of glucose to provide the building blocks for all this new cell division.5. How It Has Been Targeted in CancerThis pathway is one of the most successfully "drugged" targets in oncology. The strategy is to create "roadblocks" at different steps.Clinical Targets (Approved for Patients):Targeting the Receptor (EGFR):Monoclonal Antibodies (e.g., Cetuximab): These drugs are large proteins that act like a "cap," binding to the outside of EGFR and blocking the growth factor from ever binding.Tyrosine Kinase Inhibitors (TKIs) (e.g., Osimertinib, Gefitinib): These are small molecules that get inside the cell and "clog" the receptor's internal "kinase engine," shutting it down even if it's mutated.Targeting the Cascade (RAF/MEK):BRAF Inhibitors (e.g., Vemurafenib): Used in melanomas with the BRAF V600E mutation.MEK Inhibitors (e.g., Trametinib): Target the next step down. These are often used in combination with BRAF inhibitors to prevent resistance.Targeting the Switch (RAS):KRAS G12C Inhibitors (e.g., Sotorasib, Adagrasib): A massive recent breakthrough. These drugs directly bind to the mutant KRAS G12C protein (which was once thought "undruggable") and lock it in the "off" state.Pre-clinical Targets (In Development):New RAS Inhibitors: Scientists are racing to develop drugs for the other, more common RAS mutations (like G12D and G12V)."Pan-RAS" Inhibitors: Drugs that could block all forms of mutant RAS.Targeting "Helper" Proteins: Drugs that block SOS1 (the "on" switch helper) or SHP2 (another key activator) are in clinical trials to prevent RAS from being activated in the first place. |
| Front | Why do you think telomerase inhibitors are so toxic |
| Back | This is a critical problem in oncology. Telomerase inhibitors are so toxic because telomerase is not a cancer-specific target.While most of our body's normal, "differentiated" cells (like muscle or nerve cells) have telomerase switched off, it is highly active in several vital, normal stem cell populations.These inhibitors are "on-target" but "off-tumour." They hit the right enzyme, but in the wrong (healthy) tissues, leading to severe side effects.The Core Problem: Hitting Normal Stem CellsTelomerase's job is to maintain telomere length (the "caps" on our chromosomes) in cells that need to divide many, many times. Cancer cells reactivate it to become immortal.Unfortunately, our most essential normal tissues also rely on this exact same mechanism to function.Where the Toxicity Comes FromInhibiting telomerase causes a "delayed" cell death. The stem cells don't die immediately; they just stop being able to replenish their telomeres. With each division, their telomeres get shorter, until they hit a critical length and are forced to stop dividing (senescence) or die (apoptosis).This "delayed fuse" leads to the progressive failure of the body's highest-turnover tissues.1. π©Έ Bone Marrow (Hematopoietic Stem Cells)This is the most severe and life-limiting toxicity.What they do: These stem cells are in a constant state of division to create all of our blood and immune cells (red blood cells, white blood cells, and platelets).Effect of Inhibitor: The stem cell pool collapses.Clinical Result: Myelosuppression (bone marrow failure).Anemia (no red blood cells) β severe fatigue.Neutropenia (no neutrophils) β life-threatening infections.Thrombocytopenia (no platelets) β risk of catastrophic bleeding.2. π€’ Gut Lining (Intestinal Stem Cells)What they do: The lining of your gut replaces itself every 3-5 days. This is driven by an incredibly active population of intestinal crypt stem cells.Effect of Inhibitor: The stem cells fail, and the gut lining cannot be repaired.Clinical Result: Severe GI Toxicity.Mucositis: Painful and deep ulceration of the mouth, oesophagus, and intestines.Diarrhoea: Inability to absorb nutrients or water.3. π‘οΈ Immune System (Lymphocytes)What they do: When you get an infection, your T-cells and B-cells (lymphocytes) must divide rapidly to mount an immune response. This proliferation requires telomerase.Effect of Inhibitor: The immune response fails.Clinical Result: Immunosuppression, further increasing the risk of infection already caused by neutropenia.In short, telomerase inhibitors are toxic because they attack the very stem cells we need for basic life functions: making blood, maintaining our gut, and running our immune system. |