Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science (New York, N.Y.)	383	6682	2024 Feb 02	eadi5798	Science

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
NX-2127	NX-2127	5	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
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
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