Reference Detail

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