Master cancer pharmacology essentials: cell cycle, oncogenes, tumor suppressors, and key drug targets. Understand the molecular basis of cancer & targeted thera
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 (5-FU) — inhibits thymidylate synthase → no thymidine → no DNA. Also Capecitabine (oral prodrug of 5-FU). Cytarabine (Ara-C) — used in leukemia. - Purine analogues: 6-Mercaptopurine (6-MP) — used in ALL. Fludarabine — used in CLL. - Side effects: myelosuppression, mucositis, diarrhea, hepatotoxicity. Methotrexate — pulmonary toxicity, renal toxicity. 3. Antitumor Antibiotics - Natural products derived from Streptomyces bacteria. - Mechanism: intercalate DNA (insert between base pairs), inhibit topoisomerase II, generate free radicals. - Examples: - Doxorubicin (Adriamycin) — most important. Cardiotoxicity is dose-limiting — causes dilated cardiomyopathy. Prevented with dexrazoxane. - Bleomycin — causes pulmonary fibrosis (dose-limiting). Used in Hodgkin lymphoma (ABVD regimen). - Dactinomycin — used in Wilms tumor, Ewing sarcoma. - Mitomycin C — causes delayed myelosuppression. 4. Topoisomerase Inhibitors - Topoisomerases relieve torsional stress in DNA during replication. Inhibiting them causes DNA strand breaks. - Topoisomerase I inhibitors: Irinotecan, Topotecan. Side effects: diarrhea (irinotecan — treat with loperamide), myelosuppression. - Topoisomerase II inhibitors: Etoposide, Teniposide. Used in lung cancer, testicular cancer, lymphomas. Risk of secondary AML. 5. Mitotic Inhibitors (Spindle Poisons) - Target microtubules of the mitotic spindle — block M phase. - Vinca alkaloids (Vincristine, Vinblastine, Vinorelbine) — inhibit tubulin polymerization → prevent spindle formation → cell arrested in mitosis. - Vincristine: dose-limiting toxicity is peripheral neuropathy (NOT myelosuppression — important exam point). - Vinblastine: dose-limiting toxicity IS myelosuppression. - Taxanes (Paclitaxel, Docetaxel) — opposite mechanism: stabilize microtubules → prevent depolymerization → spindle cannot disassemble → cell stuck in mitosis. - Side effects: peripheral neuropathy, myelosuppression, hypersensitivity reactions (premedicate with corticosteroids and antihistamines). --- B. Targeted Therapy Works by specifically targeting molecular abnormalities in cancer cells — more selective, fewer side effects than cytotoxic chemo. 1. Tyrosine Kinase Inhibitors (TKIs) - Block overactive kinase receptors that drive tumor growth. Drug Target Cancer --- --- --- Imatinib (Gleevec) BCR-ABL, c-KIT, PDGFR CML, GIST Erlotinib, Gefitinib EGFR NSCLC Lapatinib HER2, EGFR Breast cancer Sorafenib RAF, VEGFR Renal cell, hepatocellular Sunitinib VEGFR, PDGFR, c-KIT Renal cell, GIST Vemurafenib BRAF V600E Melanoma - Resistance: common problem — mutations in target (e.g., T315I mutation in BCR-ABL resists imatinib → use ponatinib). 2. Monoclonal Antibodies (mAbs) - Large proteins that bind specific targets on cancer cells or their environment. - Naming: -mab suffix. -xi- = chimeric, -zu- = humanized, -u- = fully human. Drug Target Cancer --- --- --- Trastuzumab (Herceptin) HER2 Breast, gastric Beva