Cancer Cell Biology and Drug Targets
Cancer arises from genetic alterations that dysregulate cell proliferation, survival, and death, creating exploitable drug targets across multiple pathways.
## Overview
Cancer is fundamentally a disease of dysregulated cell growth resulting from somatic mutations in genes controlling proliferation, differentiation, and apoptosis. Understanding the molecular biology of malignant cells reveals the rational basis for targeted therapies and explains why certain tumors respond to specific drugs.
## Oncogenes and Tumor Suppressors
Proto-oncogenes encode proteins that promote cell growth; mutations convert them into constitutively active oncogenes. Examples include RAS (mutated in ~30% of cancers), BCR-ABL fusion in CML, and HER2 amplification in breast cancer. Tumor suppressor genes (TP53, RB1, BRCA1/2) restrain proliferation; loss-of-function mutations remove these brakes. The two-hit hypothesis explains why both alleles must be inactivated for full tumor suppressor loss.
## Cell Cycle as a Drug Target
The cell cycle progresses through G1, S (DNA synthesis), G2, and M phases, regulated by cyclin-CDK complexes. CDK4/6 inhibitors (palbociclib, ribociclib) block G1→S transition in HR+ breast cancer. CDK4/6 phosphorylates RB, releasing E2F transcription factors; inhibiting this step halts proliferation. Checkpoints at G1/S and G2/M can be exploited pharmacologically to increase tumor cell death.
## Apoptosis Pathways
The intrinsic (mitochondrial) apoptosis pathway is regulated by BCL-2 family proteins. BCL-2 overexpression in follicular lymphoma prevents apoptosis. Venetoclax is a BH3-mimetic that inhibits BCL-2, restoring apoptosis. The extrinsic pathway via death receptors (TRAIL, FAS) represents another therapeutic avenue currently under investigation.
## DNA Repair as a Target
Homologous recombination deficiency in BRCA1/2-mutated tumors creates synthetic lethality with PARP inhibitors. When HR is defective, tumors become dependent on PARP-mediated base excision repair; blocking PARP causes lethal DNA double-strand break accumulation selectively in cancer cells.
## Key Takeaways
- Oncogenes drive proliferation; tumor suppressors inhibit it — both are exploitable drug targets
- Cell cycle CDK complexes regulate G1/S and G2/M transitions and are targeted by CDK4/6 inhibitors
- BCL-2 family proteins control intrinsic apoptosis; BH3-mimetics restore cell death
- Synthetic lethality (BRCA + PARP inhibition) exemplifies precision oncology targeting