Activation of the MAPK pathway mediates resistance to PI3K inhibitors in chronic lymphocytic leukemia (cll).

Inhibitors of Bruton's tyrosine kinase (BTKi) and phosphatidylinositol 3-kinase delta (PI3Kδi) that target the B cell receptor (BCR) signaling pathway have revolutionized the treatment of chronic lymphocytic leukemia (CLL). While mutations associated with resistance to BTK inhibitors have been identified, limited data are available on mechanisms of resistance to PI3Kδi. Here we present findings from longitudinal whole-exome sequencing of multiply relapsed CLL patients (Ncases=28) enrolled in PI3Ki trials. The non-responder subgroup was characterized by baseline activating mutations in MAP2K1, BRAF and KRAS in 60% of patients. PI3Kδ inhibition failed to inhibit ERK phosphorylation (pERK) in non-responder CLL cells with and without mutations, while treatment with MEKi rescued ERK inhibition. Overexpression of MAP2K1 mutants in vitro led to increased basal and inducible pERK and resistance to idelalisib. These data demonstrate that MAPK/ERK activation plays a key role in resistance to PI3Kδi in CLL and provide rationale for combination therapy with PI3Kδ and ERK inhibitors.