Drug Mechanism of Action Across Oncology Indications: A Comprehensive Table
The most effective way to understand drug mechanisms of action (MOA) across different oncology indications is through a comprehensive two-way table that maps drug targets/pathways against tumor types, providing insights into how various therapeutic approaches work across cancer types.
Drug Target/Pathway vs. Tumor Type Table
Targeted Therapies
| Drug Target/Pathway | Breast Cancer | Lung Cancer | Colorectal Cancer | Gastric/GEJ Cancer | Head & Neck Cancer | Other Tumors |
|---|---|---|---|---|---|---|
| HER2 Pathway | Trastuzumab inhibits HER2 receptor signaling, mediates ADCC [1] | Limited role | Limited role | Trastuzumab + chemotherapy in HER2+ disease [2] | Limited role | Various solid tumors |
| EGFR Pathway | Limited role | Gefitinib inhibits EGFR kinase activity in EGFR-mutant NSCLC [3] | Limited efficacy | Limited role | Significant target | Various carcinomas |
| Angiogenesis (VEGF) | Combined with chemotherapy | Combined with chemotherapy | Target for antiangiogenic therapy [2] | Limited role | Limited role | Cervical cancer with bevacizumab [2] |
| Proteasome | Limited role | Limited role | Limited role | Limited role | Limited role | Multiple myeloma [2] |
Immunotherapy Approaches
| Immune Checkpoint | Breast Cancer | Lung Cancer | Colorectal Cancer | Gastric/GEJ Cancer | Head & Neck Cancer | Other Tumors |
|---|---|---|---|---|---|---|
| PD-1/PD-L1 | TNBC with pembrolizumab + chemo [2] | Multiple approvals with pembrolizumab, nivolumab, atezolizumab [2] | MSI-high tumors | Nivolumab in combination [2] | Pembrolizumab + chemo [2] | Cervical, biliary tract [2] |
| CTLA-4 | Limited role | Nivolumab + ipilimumab in NSCLC [2] | Limited role | Limited role | Limited role | Melanoma |
| Combined ICIs | Limited role | Nivolumab + ipilimumab + chemo in NSCLC [2] | Limited role | Limited role | Limited role | Various solid tumors |
Chemotherapy Mechanisms
| Mechanism | Breast Cancer | Lung Cancer | Colorectal Cancer | Gastric Cancer | Head & Neck Cancer | Other Tumors |
|---|---|---|---|---|---|---|
| DNA Damage/Crosslinking | Anthracyclines, platinum agents [2] | Platinum agents [2] | Oxaliplatin [2] | Platinum agents [2] | Platinum agents [2] | Various solid tumors |
| Antimetabolites | 5-FU, methotrexate [2] | Pemetrexed [2] | 5-FU, capecitabine [2] | 5-FU [2] | 5-FU [2] | Various solid tumors |
| Microtubule Disruption | Taxanes (paclitaxel, docetaxel) [2] | Taxanes [2] | Limited role | Taxanes [2] | Taxanes [2] | Various solid tumors |
| Topoisomerase Inhibition | Limited role | Irinotecan [2] | Irinotecan [2] | Irinotecan [2] | Limited role | Various solid tumors |
Mechanisms of Action and Clinical Implications
Targeted Therapies
- HER2 Inhibitors: Trastuzumab binds to HER2 receptors, inhibiting cell proliferation and mediating antibody-dependent cellular cytotoxicity (ADCC) in HER2-overexpressing tumors 1
- EGFR Inhibitors: Gefitinib reversibly inhibits kinase activity of wild-type and mutant EGFR, with higher binding affinity for activating mutations (exon 19 deletion, L858R) in NSCLC 3
- Antiangiogenic Agents: Prevent formation of new blood vessels by inhibiting VEGF, potentially disrupting neurogenesis and causing vascular dysfunction 2
- Proteasome Inhibitors: Prevent breakdown of pro-apoptotic proteins, enabling programmed cell death in cancer cells, but may cause amyloid-β aggregation from disruption of proteostasis 2
Immunotherapy
- Immune Checkpoint Inhibitors: Block checkpoint proteins (PD-1/PD-L1, CTLA-4) from binding with partner T cells, enabling cancer cell killing by the immune system 2
- CAR T-cell Therapy: Genetically modified T cells with chimeric antigen receptors that bind to and kill cancer cells, though may cause neuronal damage through cross-reaction with CNS-borne antigens 2
- Combined Immunotherapy: Multiple checkpoint blockade (e.g., nivolumab + ipilimumab) shows synergistic effects in certain tumors like NSCLC 2
Chemotherapy
- Anthracyclines: Block DNA damage repair and disrupt cell cycle, causing mitochondrial dysfunction and oxidative stress 2
- Platinum Agents: Crosslink DNA strands to inhibit DNA function and synthesis, causing apoptosis 2
- Taxanes: Promote microtubule assembly and block dissociation, preventing mitosis in cancer cells 2
- Antimetabolites: Interrupt synthesis of DNA and RNA in cancer cells, with agents like methotrexate impairing neurogenesis 2
Combination Approaches and Rationale
- Chemotherapy + Immunotherapy: Combinations show improved efficacy with modest increases in toxicity across multiple tumor types 2
- Targeted Therapy + Chemotherapy: Combinations like trastuzumab with chemotherapy in HER2+ gastric cancer improve outcomes 2
- Multiple Targeted Agents: Combinations targeting different pathways may overcome resistance mechanisms 2
Toxicity Considerations by Drug Class
- Chemotherapy-specific: Neutropenia, anemia, thrombocytopenia, peripheral neuropathy 2
- Immunotherapy-specific: Thyroid dysfunction, pneumonitis, immune-related adverse events 2
- Combination-induced: Increased risk of diarrhea (RR 1.19), rash (RR 1.56), and liver enzyme elevation (RR 1.13) when combining immunotherapy with chemotherapy 2
Future Directions
- Phenotypic Profiling: Using cell-based assays to identify cellular response "fingerprints" that identify mechanisms of action for both efficacy and safety 2
- Pathway-Based Approaches: Integrating diverse datasets from disease names and clinical symptoms through cell types and pathways to genes, mutations, and drugs 2
- Drug Repurposing: Using network-based models to study treatment patterns and identify potential new indications for existing drugs 4, 5
This table provides a holistic view of drug mechanisms of action across oncology indications, highlighting how different therapeutic approaches target specific pathways in various tumor types.