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Principles of targeted therapy — kinase inhibitors, antibodies, ADCs and bispecifics
Targeted therapy hits a molecule the tumour depends on: small molecules (names ending in nib) enter the cell and inhibit kinases, antibodies (mab) bind receptors from outside, and ADCs deliver a toxin directly to a cell expressing the target — and each family has a typical toxicity.
Why it matters in the exam
The bank asks a lot about mechanisms and side effects of targeted drugs: what PI3K does and what alpelisib inhibits, in which cell-cycle phase cells treated with CDK4/6 inhibitors arrest, the mechanism of T-DM1 and T-DXd, which drug is a bispecific antibody, and which drug binds its enzyme reversibly.
The right answer is usually found by linking the target to the toxicity: blocking EGFR harms skin and bowel, blocking VEGF raises blood pressure and causes proteinuria, blocking PI3K raises glucose, and FGFR inhibitors raise phosphate. It is also worth remembering the general resistance mechanisms — mutation in the target, a bypass pathway and histological change.
Key points
- Small molecules inhibit kinases inside the cell, and antibodies bind receptors outside the cell or recruit the immune system.
- First-generation EGFR inhibitors bind reversibly, while osimertinib and afatinib bind covalently and irreversibly.
- CDK4/6 inhibitors arrest the cell in G1, and alpelisib inhibits PI3K and raises blood glucose.
- ADCs deliver a toxin directly to the cell; T-DXd also affects neighbouring cells and may cause interstitial lung disease.
- Bispecific antibodies that recruit T cells may cause cytokine release syndrome and neurotoxicity.
Summary table
| Family | Mechanism | Typical toxicity and examples |
|---|---|---|
| EGFR inhibitors | Erlotinib and gefitinib bind reversibly; afatinib and osimertinib bind covalently and irreversibly | Acneiform rash, diarrhoea, paronychia; with antibodies — also hypomagnesaemia |
| VEGF and VEGFR inhibitors | Bevacizumab (antibody) and tyrosine kinase inhibitors | Hypertension, proteinuria, bleeding, thrombosis, bowel perforation and delayed wound healing; with tyrosine kinase inhibitors also hypothyroidism |
| PI3K, AKT and mTOR pathway | PI3K phosphorylates membrane lipids and activates AKT; alpelisib inhibits the α subunit | Hyperglycaemia, rash and diarrhoea; with mTOR inhibitors — stomatitis and pneumonitis |
| CDK4/6 inhibitors | Prevent RB phosphorylation and arrest the cell in G1 | Neutropenia; ribociclib — QT prolongation and liver injury; abemaciclib — diarrhoea |
| PARP inhibitors | Trapping PARP on DNA and synthetic lethality in cells lacking homologous recombination | Anaemia and fatigue; rare risk of MDS and AML |
| ADC — antibody-drug conjugate | Antibody, linker and toxin; with T-DXd the toxin also passes to neighbouring cells | T-DM1: thrombocytopenia and liver injury; T-DXd: interstitial lung disease |
| Bispecific antibodies and FGFR inhibitors | Link a T cell (CD3) to the tumour cell: blinatumomab, teclistamab, tarlatamab | Bispecifics: cytokine release syndrome and neurotoxicity; FGFR inhibitors: raised phosphate and retinal injury |
Free exam questions
איזו מהתרופות הבאות ?נקשרת לאנזים במנגנון הפיך (the question as examined, in Hebrew)
- א. אוסימרטיניב
- ב. גפיטיניב
- ג. סוטורסיב
- ד. אדגרסיב
מטופל המאובחן בסרטן מעי גס גרורתי מסוג RAS WILD TYPE , מביע את רצונו בטיפול אשר יהיה ללא ביטוי חיצוני כדי לא להסגיר ל סביבה את מחלתו. איזה מהמשלבים הבאים מומלץ? (the question as examined, in Hebrew)
- א. FOLFOX – CETUXIMAB
- ב. FOLFOX – BEVACIZUMAB
- ג. FOLRIFI - CETUXIMAB
- ד. FOLFIRI - BEVACIZUMAB
In the full version for subscribers
- A simple algorithm
- Memory aid
- Exam traps
- 5 review cards
- Enough for IMLE
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Sources
- DeVita, Hellman and Rosenberg's Cancer: Principles and Practice of Oncology, 12th ed. (2023) — Targeted therapy; Antibody-drug conjugates
- Chabner and Longo, Cancer Chemotherapy, Immunotherapy and Biotherapy: Principles and Practice, 6th ed. (2018) — Kinase inhibitors; Monoclonal antibodies
- ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), 2018 — Levels of evidence
Sources are given for further reading; the text is written afresh and not copied from them.
Reviewed by the Examqo AI Professor · 2026-11-06. The text may contain errors; when in doubt, check the source.