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Ref Type Journal Article
PMID (36287227)
Authors Naeem A, Utro F, Wang Q, Cha J, Vihinen M, Martindale S, Zhou Y, Ren Y, Tyekucheva S, Kim AS, Fernandes SM, Saksena G, Rhrissorrakrai K, Levovitz C, Danysh BP, Slowik K, Jacobs RA, Davids MS, Lederer JA, Zain R, Smith CIE, Leshchiner I, Parida L, Getz G, Brown JR
Title Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to resistance.
Journal Vol Issue Date Pages Journal Short Title
Blood advances 7 9 2023 May 09 1929-1943 Blood Adv
URL
Abstract Text Covalent inhibitors of Bruton tyrosine kinase (BTK) have transformed the therapy of chronic lymphocytic leukemia (CLL), but continuous therapy has been complicated by the development of resistance. The most common resistance mechanism in patients whose disease progresses on covalent BTK inhibitors (BTKis) is a mutation in the BTK 481 cysteine residue to which the inhibitors bind covalently. Pirtobrutinib is a highly selective, noncovalent BTKi with substantial clinical activity in patients whose disease has progressed on covalent BTKi, regardless of BTK mutation status. Using in vitro ibrutinib-resistant models and cells from patients with CLL, we show that pirtobrutinib potently inhibits BTK-mediated functions including B-cell receptor (BCR) signaling, cell viability, and CCL3/CCL4 chemokine production in both BTK wild-type and C481S mutant CLL cells. We demonstrate that primary CLL cells from responding patients on the pirtobrutinib trial show reduced BCR signaling, cell survival, and CCL3/CCL4 chemokine secretion. At time of progression, these primary CLL cells show increasing resistance to pirtobrutinib in signaling inhibition, cell viability, and cytokine production. We employed longitudinal whole-exome sequencing on 2 patients whose disease progressed on pirtobrutinib and identified selection of alternative-site BTK mutations, providing clinical evidence that secondary BTK mutations lead to resistance to noncovalent BTKis.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BTK T474I BTK C481S chronic lymphocytic leukemia predicted - resistant Pirtobrutinib Case Reports/Case Series Actionable In a clinical case study, Jaypirca (pirtobrutinib) treatment resulted in a continued decrease of cancer cell fraction (CCF) of a clone of cells harboring BTK C481S but persistent increase of a clone harboring BTK T474I in a patient with chronic lymphocytic leukemia, as well as low-level CCF increase of BTK T474L, and BTK M477I (PMID: 36287227). 36287227
BTK C481S chronic lymphocytic leukemia sensitive Pirtobrutinib Preclinical - Patient cell culture Actionable In a preclinical study, Jaypirca (pirtobrutinib) inhibited proliferation of patient-derived chronic lymphocytic leukemia cells harboring BTK C481S in culture (PMID: 36287227). 36287227
BTK C481S chronic lymphocytic leukemia predicted - resistant Acalabrutinib Case Reports/Case Series Actionable In a clinical case study, a patient with chronic lymphocytic leukemia progressed on treatment with Calquence (acalabrutinib), and was subsequently found to have acquired BTK C481S (PMID: 36287227). 36287227