On-target resistance mutations (gatekeeper, solvent-front, compound)
When a cancer becomes resistant to a targeted pill, it often does so by changing the exact spot where the drug binds: a 'gatekeeper' or 'solvent-front' mutation. Next-generation drugs are designed to fit around these changes.
Gatekeeper mutations (EGFR T790M, ABL T315I, KIT T670I) alter a residue at the entrance to the ATP pocket; solvent-front mutations (ALK G1202R, ROS1 G2032R, NTRK G595R) change the drug's contact surface; compound mutations stack two or more changes and defeat successive drug generations. Each generation of inhibitor answers the last: osimertinib for T790M, lorlatinib and neladalkib for G1202R, ponatinib and asciminib for T315I, repotrectinib for G2032R. Re-biopsy or ctDNA at progression identifies the mutation and guides the switch; off-target bypass (MET amplification, histologic transformation) is the other main route.
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not linked directly; found by shared links- TermPhiladelphia chromosome (Ph+, BCR::ABL1)
Shares Asciminib, Ponatinib, Tyrosine kinase inhibitor (TKI).
- PairingSequence: targeted therapy before immunotherapy in driver-positive NSCLC
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- CollectionLUNGevity Foundation (and GO2 for Lung Cancer)
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- PersonMyung-Ju Ahn
Shares ALK, Osimertinib, EGFR.