4.6 Drug Effects on Gene Expression
Many drugs exert therapeutic effects by modulating gene transcription, either directly (nuclear receptors, transcription factor inhibitors) or indirectly (signaling cascades). Understanding transcriptional regulation is essential for epigenetic therapies, cancer treatment, and immunomodulation.
Transcription Factor Pathways Targeted by Drugs
NF-κB (Nuclear Factor kappa B)
Role: Master regulator of inflammation and immune response; pro-survival factor in cancer
Activation: TNF-α, IL-1β, LPS → IKK phosphorylates IκB → IκB degradation → NF-κB (p50/p65) translocates to nucleus
Target genes: Cytokines (TNF-α, IL-1, IL-6), adhesion molecules (ICAM-1, VCAM-1), COX-2, iNOS, anti-apoptotic proteins (Bcl-2, Bcl-xL)
Drugs: Glucocorticoids (↑ IκB synthesis, ↓ NF-κB activity), proteasome inhibitors (bortezomib - blocks IκB degradation, multiple myeloma), aspirin/NSAIDs (indirect inhibition)
AP-1 (Activator Protein-1)
Composition: Jun/Fos heterodimers or Jun homodimers
Activation: MAPK pathway (ERK, JNK, p38) → phosphorylation of Jun/Fos
Functions: Cell proliferation, differentiation, apoptosis, inflammation
Drugs: MEK inhibitors (trametinib, cobimetinib - block ERK activation, melanoma), JNK inhibitors (investigational)
CREB (cAMP Response Element Binding Protein)
Activation: PKA, CaMKII, or PKC phosphorylate CREB at Ser133 → recruits CBP/p300 coactivators
Target genes: c-fos, BDNF, somatostatin, gluconeogenesis enzymes
Drugs: Any drug ↑ cAMP (β-agonists, PDE inhibitors), forskolin (direct AC activator, research)
HIF-1α (Hypoxia-Inducible Factor)
Regulation: Normoxia → PHD hydroxylates HIF-1α → VHL-mediated ubiquitination/degradation; Hypoxia → stabilization
Target genes: VEGF, EPO, glycolytic enzymes, glucose transporters
Drugs: HIF-PHD inhibitors (roxadustat, daprodustat - anemia in CKD, ↑ EPO), VEGF inhibitors (bevacizumab - block HIF target)
NFAT (Nuclear Factor of Activated T-cells)
Activation: Ca²⁺ → calcineurin (phosphatase) → NFAT dephosphorylation → nuclear translocation
Role: T-cell activation, IL-2 expression
Drugs: Cyclosporine, tacrolimus (calcineurin inhibitors - block NFAT activation, immunosuppression after transplant)
Epigenetic Modifiers
Histone Deacetylase (HDAC) Inhibitors
Mechanism: Inhibit HDACs → ↑ histone acetylation → open chromatin → ↑ gene transcription
Effects: Tumor suppressor gene reactivation, differentiation, apoptosis
Drugs:
- • Vorinostat (SAHA) - cutaneous T-cell lymphoma
- • Romidepsin - cutaneous/peripheral T-cell lymphoma
- • Panobinostat - multiple myeloma
- • Valproic acid - bipolar disorder, epilepsy (also HDAC inhibitor)
DNA Methyltransferase (DNMT) Inhibitors
Mechanism: Inhibit DNA methylation → reactivation of silenced genes (e.g., tumor suppressors)
Drugs:
- • Azacitidine (5-azacytidine) - myelodysplastic syndrome (MDS), AML
- • Decitabine (5-aza-2'-deoxycytidine) - MDS, AML
Mechanism: Incorporate into DNA → trap DNMTs → DNA hypomethylation
Histone Methyltransferase Inhibitors
EZH2 inhibitors: Tazemetostat (follicular lymphoma, INI1-mutated cancers)
DOT1L inhibitors: Pinometostat (MLL-rearranged leukemia, investigational)
Mechanism: Block specific histone methylation marks that silence tumor suppressors
BET Bromodomain Inhibitors
Mechanism: Block BRD4 binding to acetylated histones → disrupt MYC transcription
Drugs: JQ1 (research tool), investigational agents for hematologic malignancies
Drugs Affecting mRNA and Protein Synthesis
mRNA Translation Inhibitors
mTOR inhibitors: Rapamycin (sirolimus), everolimus, temsirolimus
Mechanism: mTORC1 inhibition → ↓ cap-dependent translation, ↓ protein synthesis
Uses: Immunosuppression (transplant), cancer (RCC, breast), tuberous sclerosis
Proteasome Inhibitors
Drugs: Bortezomib, carfilzomib, ixazomib (multiple myeloma)
Mechanism: Inhibit 26S proteasome → accumulation of misfolded proteins → ER stress → apoptosis
Also affects: NF-κB (blocks IκB degradation), p53 (blocks degradation), cell cycle regulators
Antisense Oligonucleotides (ASOs)
Mechanism: Synthetic DNA/RNA complementary to target mRNA → RNase H-mediated degradation or translation blockade
Examples:
- • Nusinersen (spinal muscular atrophy - corrects SMN2 splicing)
- • Mipomersen (familial hypercholesterolemia - ↓ ApoB-100)
- • Inotersen (hereditary transthyretin amyloidosis)
RNA Interference (siRNA)
Mechanism: Small interfering RNA → RISC complex → mRNA cleavage
Examples: Patisiran (hereditary transthyretin amyloidosis - targets TTR mRNA), givosiran (acute hepatic porphyria - targets ALAS1)
Pharmacogenomics: Gene Variants Affecting Drug Response
Cytochrome P450 Polymorphisms
CYP2D6: Poor metabolizers (7% Caucasians) - ↑ toxicity from codeine prodrug (inadequate morphine), tricyclic antidepressants
CYP2C19: Affects clopidogrel activation (poor metabolizers have ↓ antiplatelet effect), proton pump inhibitors
CYP2C9: Warfarin metabolism - variants require dose adjustment
Thiopurine Methyltransferase (TPMT)
Variants: Low/absent TPMT activity (1 in 300 homozygous)
Clinical impact: Life-threatening myelosuppression from azathioprine, 6-mercaptopurine (IBD, autoimmune, ALL)
Testing: Genotype or phenotype before initiating therapy
HLA Alleles and Adverse Reactions
HLA-B*5701: Abacavir hypersensitivity (HIV therapy) - test before prescribing
HLA-B*1502: Stevens-Johnson syndrome/TEN with carbamazepine (Asian populations)
HLA-B*5801: Allopurinol severe cutaneous reactions
Warfarin Dosing Genes
CYP2C9: Metabolic inactivation (variants require ↓ dose)
VKORC1: Drug target, variants affect sensitivity
Algorithms: Incorporate genotype, age, weight, drug interactions for personalized dosing
Future Directions
CRISPR Therapeutics
Gene editing to correct disease-causing mutations. Approved: CTX001 (sickle cell disease, β-thalassemia). Investigational: many genetic diseases.
mRNA Vaccines/Therapeutics
COVID-19 vaccines validated platform. Future: cancer vaccines, protein replacement therapy, infectious diseases
Personalized Medicine
Integration of genomics, transcriptomics, proteomics to select optimal therapy. PGx testing becoming standard of care.
Epigenetic Reprogramming
Targeted reversal of aberrant epigenetic marks in cancer, aging, neurodegeneration. Next-gen selective inhibitors.