Targeted therapy resistance

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Targeted Therapy Resistance refers to the phenomenon where cancer cells that initially respond to targeted therapy (drugs designed to inhibit specific molecular pathways or mutations driving the cancer) become unresponsive or less responsive over time. This is a major challenge in oncology.

Here’s a structured breakdown:

🔬 Mechanisms of Targeted Therapy Resistance Genetic Alterations

Secondary mutations: New mutations in the drug target that prevent binding (e.g., T790M mutation in EGFR in NSCLC).

Gene amplification: Overexpression of the target or alternate pathways (e.g., MET amplification after EGFR inhibition).

Bypass Signaling Pathways

Cancer activates alternative growth pathways (e.g., PI3K/AKT/mTOR, MAPK) to maintain proliferation.

Phenotypic Changes

Epithelial-to-mesenchymal transition (EMT): Cells become more invasive and less sensitive.

Histologic transformation: Example—NSCLC transforming into small cell lung cancer.

Tumor Microenvironment (TME)

Stromal cells, immune cells, and cytokines in the TME can protect tumor cells from drugs.

Drug Efflux and Metabolism

Increased expression of efflux pumps (e.g., P-glycoprotein) reduces intracellular drug concentration.

🧪 Examples in Clinical Practice EGFR inhibitors in lung cancer → Resistance via T790M or MET amplification.

BRAF inhibitors in melanoma → Reactivation of MAPK pathway.

ALK inhibitors → Resistance via ALK mutations or bypass tracks like EGFR or KIT.

🔄 Strategies to Overcome Resistance Next-generation inhibitors

E.g., Osimertinib for EGFR T790M mutations.

Combination therapies

Targeting primary and bypass pathways simultaneously.

Immunotherapy

Can be used when targeted options are exhausted.

Biopsy and molecular profiling at progression

Essential for understanding mechanisms and adapting treatment.