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Ref Type | Journal Article | ||||||||||||
PMID | (38301010) | ||||||||||||
Authors | Montoya S, Bourcier J, Noviski M, Lu H, Thompson MC, Chirino A, Jahn J, Sondhi AK, Gajewski S, Tan YSM, Yung S, Urban A, Wang E, Han C, Mi X, Kim WJ, Sievers Q, Auger P, Bousquet H, Brathaban N, Bravo B, Gessner M, Guiducci C, Iuliano JN, Kane T, Mukerji R, Reddy PJ, Powers J, Sanchez Garcia de Los Rios M, Ye J, Barrientos Risso C, Tsai D, Pardo G, Notti RQ, Pardo A, Affer M, Nawaratne V, Totiger TM, Pena-Velasquez C, Rhodes JM, Zelenetz AD, Alencar A, Roeker LE, Mehta S, Garippa R, Linley A, Soni RK, Skånland SS, Brown RJ, Mato AR, Hansen GM, Abdel-Wahab O, Taylor J | ||||||||||||
Title | Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127. | ||||||||||||
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Abstract Text | 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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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NX-2127 | NX 2127|NX2127 | BTK inhibitor 37 | NX-2127 is a small molecule that induces degradation of BTK, which may lead to inhibition of the growth of malignant B-cells (PMID: 38301010). |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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BTK | C481S | missense | no effect | BTK C481S lies within the protein kinase domain of the Btk protein (UniProt.org). C481S demonstrates kinase activity similar to wild-type Btk (PMID: 38301010), but confers Imbruvica (ibrutinib) resistance in cell culture (PMID: 27282255, PMID: 28573668) through interference of drug binding (PMID: 25189416, PMID: 23940282). | Y |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
---|---|---|---|---|---|---|---|
BTK T474I | diffuse large B-cell lymphoma | resistant | Acalabrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK T474I demonstrated resistance to Calquence (acalabrutinib) in culture (PMID: 38301010). | 38301010 |
BTK C481S | diffuse large B-cell lymphoma | resistant | Zanubrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK C481S demonstrated resistance to Brukinsa (zanubrutinib) in culture (PMID: 38301010). | 38301010 |
BTK T474I | diffuse large B-cell lymphoma | resistant | Pirtobrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK T474I demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 38301010). | 38301010 |
BTK C481S | diffuse large B-cell lymphoma | resistant | Acalabrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK C481S demonstrated resistance to Calquence (acalabrutinib) in culture (PMID: 38301010). | 38301010 |
BTK L528W | diffuse large B-cell lymphoma | resistant | Zanubrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK L528W demonstrated resistance to Brukinsa (zanubrutinib) in culture (PMID: 38301010). | 38301010 |
BTK V416L | diffuse large B-cell lymphoma | resistant | Pirtobrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK V416L demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 38301010). | 38301010 |
BTK L528W | diffuse large B-cell lymphoma | resistant | Pirtobrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK L528W demonstrated resistance to Jaypirca (pirtobrutinib) in culture (PMID: 38301010). | 38301010 |
BTK C481S | diffuse large B-cell lymphoma | sensitive | NX-2127 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, NX-2127 inhibited viability of a diffuse large B-cell lymphoma cell line expressing BTK C481S in culture (PMID: 38301010). | 38301010 |
BTK L528W | diffuse large B-cell lymphoma | resistant | Ibrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK L528W demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 38301010). | 38301010 |
BTK C481S | diffuse large B-cell lymphoma | resistant | Ibrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK C481S demonstrated resistance to Imbruvica (ibrutinib) in culture (PMID: 38301010). | 38301010 |
BTK V416L | diffuse large B-cell lymphoma | sensitive | NX-2127 | Preclinical - Cell culture | Actionable | In a preclinical study, NX-2127 inhibited viability of a diffuse large B-cell lymphoma cell line expressing BTK V416L in culture (PMID: 38301010). | 38301010 |
BTK L528W | diffuse large B-cell lymphoma | sensitive | NX-2127 | Preclinical - Cell culture | Actionable | In a preclinical study, NX-2127 inhibited viability of a diffuse large B-cell lymphoma cell line expressing BTK L528W in culture (PMID: 38301010). | 38301010 |
BTK V416L | diffuse large B-cell lymphoma | resistant | Acalabrutinib | Preclinical - Cell culture | Actionable | In a preclinical study, a diffuse large B-cell lymphoma cell line expressing BTK V416L demonstrated resistance to Calquence (acalabrutinib) in culture (PMID: 38301010). | 38301010 |
BTK T474I | diffuse large B-cell lymphoma | sensitive | NX-2127 | Preclinical - Cell culture | Actionable | In a preclinical study, NX-2127 inhibited viability of a diffuse large B-cell lymphoma cell line expressing BTK T474I in culture (PMID: 38301010). | 38301010 |
BTK C481R BTK L528W | chronic lymphocytic leukemia | predicted - sensitive | NX-2127 | Case Reports/Case Series | Actionable | In a Phase I trial, NX-2127 treatment resulted in a partial response in a patient with chronic lymphocytic leukemia harboring BTK C481R and L528W, who had progressed on prior BTK inhibitors (PMID: 38301010; NCT04830137). | 38301010 |