Cancer Pharmacology: Cell Cycle, Oncogenes & Drug Targets

CANCER PHARMACOLOGY 1. WHAT IS CANCER — THE PHARMACOLOGICAL PERSPECTIVE Cancer is uncontrolled proliferation of abnormal cells resulting from genetic mutations that disrupt normal cell cycle regulation. From a pharmacological standpoint, understanding cancer means understanding what goes wrong at the molecular level so you know what drugs target and why. Key characteristics of cancer cells (Hallmarks of Cancer — Hanahan & Weinberg): Sustaining proliferative signaling Evading growth suppressors Resisting cell death (apoptosis) Enabling replicative immortality (telomerase activation) Inducing angiogenesis Activating invasion and metastasis Reprogramming energy metabolism (Warburg effect — cancer cells prefer glycolysis even in presence of oxygen) Evading immune destruction Each hallmark is a drug target. --- 2. CELL CYCLE — MUST KNOW FOR EXAM The cell cycle has 5 phases. Chemotherapy drugs are classified by which phase they target. G1 — cell grows, prepares for DNA synthesis. Cyclin D/CDK4,6 active. S phase — DNA replication occurs. Most sensitive phase for antimetabolites. G2 — cell checks DNA before dividing. Cyclin B/CDK1 active. M phase (Mitosis) — cell physically divides. Target of vinca alkaloids and taxanes. G0 — resting phase. Cells not actively dividing. Many cancer cells hide here — hard to kill. Cell cycle checkpoints: G1/S checkpoint — p53 and RB1 operate here. Checks DNA integrity before replication. G2/M checkpoint — checks DNA is fully replicated before division. Spindle assembly checkpoint — ensures chromosomes are properly attached before separation. Cancer cells bypass these checkpoints due to mutations in p53, RB1, and cyclins. --- 3. MOLECULAR BASIS OF CANCER — ONCOGENES AND TUMOR SUPPRESSOR GENES Oncogenes Derived from normal proto-oncogenes that regulate cell growth. Mutation converts proto-oncogene into oncogene — acts like a permanently switched-on accelerator. Dominant — only one mutated allele needed. Mechanisms of activation: point mutation, gene amplification, chromosomal translocation. Key oncogenes to know: Oncogene Cancer Type Drug Target --- --- --- RAS Colorectal, lung, pancreatic Hard to target directly HER2 (ERBB2) Breast, gastric Trastuzumab (Herceptin) BCR-ABL CML (leukemia) Imatinib (Gleevec) EGFR Lung, colorectal Erlotinib, Cetuximab MYC Burkitt lymphoma, many cancers Under investigation VEGF Many solid tumors Bevacizumab Tumor Suppressor Genes (TSGs) Normally brake cell division, promote apoptosis, and repair DNA. Recessive — both alleles must be lost or inactivated (Knudson Two-Hit Hypothesis, 1971). Loss of function = brakes removed = unchecked proliferation. Key TSGs to know: Gene Function Cancer when lost --- --- --- TP53 (p53) Guardian of genome — triggers apoptosis and DNA repair 50%+ of all cancers RB1 Blocks G1/S transition Retinoblastoma, many others BRCA1/2 DNA repair (homologous recombination) Breast, ovarian APC Controls Wnt signaling Colorectal cancer PTEN Suppresses PI3K/AKT pathway Prostate, breast, endometrial BRCA1/2 clinical significance: Patients with BRCA mutations respond to PARP inhibitors (olaparib) — concept of synthetic lethality. --- 4. SIGNAL TRANSDUCTION PATHWAYS — KEY DRUG TARGETS These pathways relay growth signals from outside the cell to the nucleus. RAS-RAF-MEK-ERK pathway Growth factor binds receptor → RAS activated → RAF → MEK → ERK → nucleus → cell proliferation. Mutant RAS is permanently active — found in 30% of all human cancers. Drugs: BRAF inhibitors (vemurafenib for melanoma with BRAF V600E mutation), MEK inhibitors (trametinib). PI3K-AKT-mTOR pathway Promotes cell survival, growth, metabolism. PTEN normally suppresses this pathway. Loss of PTEN = overactive pathway. Drugs: mTOR inhibitors (everolimus, temsirolimus), PI3K inhibitors (idelalisib). JAK-STAT pathway Cytokine signaling pathway — important in hematological malignancies. Drugs: Ruxolitinib (JAK1/2 inhibitor) — used in myelofibrosis and polycythemia vera. Wnt/Beta-catenin pathway Important in colorectal cancer (APC gene mutation leads to uncontrolled Wnt signaling). Under active drug development. --- 5. CLASSIFICATION OF ANTICANCER DRUGS A. Cytotoxic Chemotherapy 1. Alkylating Agents Mechanism: form covalent bonds with DNA, cross-link DNA strands → prevent replication and transcription → cell death. Cell cycle non-specific. Examples: Cyclophosphamide (prodrug — activated by CYP450 in liver), Cisplatin, Carboplatin, Busulfan, Chlorambucil. Side effects: myelosuppression, hemorrhagic cystitis (cyclophosphamide — prevented by mesna), nephrotoxicity (cisplatin — prevent with IV hydration), nausea, alopecia, secondary leukemia. 2. Antimetabolites Mechanism: structurally similar to normal metabolites, they substitute and disrupt DNA/RNA synthesis. Cell cycle specific — S phase. Types: Folate antagonists: Methotrexate — inhibits dihydrofolate reductase (DHFR) → blocks thymidylate and purine synthesis. Rescue with folinic acid (leucovorin). Pyrimidine analogues: 5-Fluorouracil