Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.
Skye MontoyaJessie BourcierMark NoviskiHao LuMeghan C ThompsonAlexandra ChirinoThomas Jacob JahnAnya K SondhiStefan GajewskiYing Siow May TanStephanie YungAleksandra UrbanEric WangCuijuan HanXiaoli MiWon Jun KimQuinlan L SieversPaul AugerHugo BousquetNivetha BrathabanBrandon BravoMelissa GessnerCristiana GuiducciJames N IulianoTim KaneRatul MukerjiPanga Jaipal ReddyJanine PowersMateo Sanchez Garcia de Los RiosJordan YeCarla Barrientos RissoDaniel TsaiGabriel PardoRyan Q NottiAlejandro PardoMaurizio AfferVindhya NawaratneTulasigeri M TotigerCamila Pena-VelasquezJoanna M RhodesAndrew D ZelenetzAlvaro AlencarLindsey Elizabeth RoekerSanjoy MehtaRalph GarippaAdam J LinleyRajesh Kumar SoniSigrid S SkånlandRobert J BrownAnthony R MatoGwenn H HansenOmar Abdel-WahabJustin TaylorPublished in: Science (New York, N.Y.) (2024)
Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.