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CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition

2020; Springer Nature; Volume: 34; Issue: 6 Linguagem: Inglês

10.1038/s41375-020-0714-3

1476-5551

Miguel Quijada‐Álamo, María Hernández‐Sánchez, Verónica Alonso-Pérez, Ana E. Rodríguez‐Vicente, Ignacio García‐Tuñón, Marta Martín‐Izquierdo, Jesús María Hernández-Sánchez, Ana B. Herrero, José María Bastida, Laura San‐Segundo, Michaela Gruber, Juan Luis Garcı́a, Shanye Yin, Elisa ten Hacken, Rocí­o Benito, José Luis Ordóñez, Catherine J. Wu, Jesús María Hernández‐Rivas,

Immunodeficiency and Autoimmune Disorders

Abstract The deletion of 11q (del(11q)) invariably comprises ATM gene in chronic lymphocytic leukemia (CLL). Concomitant mutations in this gene in the remaining allele have been identified in 1/3 of CLL cases harboring del(11q), being the biallelic loss of ATM associated with adverse prognosis. Although the introduction of targeted BCR inhibition has significantly favored the outcomes of del(11q) patients, responses of patients harboring ATM functional loss through biallelic inactivation are unexplored, and the development of resistances to targeted therapies have been increasingly reported, urging the need to explore novel therapeutic approaches. Here, we generated isogenic CLL cell lines harboring del(11q) and ATM mutations through CRISPR/Cas9-based gene-editing. With these models, we uncovered a novel therapeutic vulnerability of del(11q)/ ATM -mutated cells to dual BCR and PARP inhibition. Ex vivo studies in the presence of stromal stimulation on 38 CLL primary samples confirmed a synergistic action of the combination of olaparib and ibrutinib in del(11q)/ ATM -mutated CLL patients. In addition, we showed that ibrutinib produced a homologous recombination repair impairment through RAD51 dysregulation, finding a synergistic link of both drugs in the DNA damage repair pathway. Our data provide a preclinical rationale for the use of this combination in CLL patients with this high-risk cytogenetic abnormality.