Targeted Therapy and Resistance

Imatinib changed oncology in 2001. It blocks the BCR-ABL kinase in chronic myeloid leukemia, turning a fatal disease into a manageable one. Since then, small-molecule inhibitors and antibodies have been developed for EGFR, HER2 (trastuzumab), BRAF, ALK, KRAS G12C and more.

Treatment now often starts with tumor sequencing to match patients to drugs.

Tumors adapt. Gatekeeper mutations (BCR-ABL T315I, EGFR T790M) block drug binding — answered by next-generation drugs like ponatinib and osimertinib. Cells can also activate bypass pathways (MET amplification in EGFR-treated lung cancer) or change cell type entirely.

Antibody–drug conjugates like trastuzumab deruxtecan deliver chemotherapy directly to cells displaying a target protein.