The majority of adult patients with acute lymphoblastic leukemia (ALL) suffer relapse, and in patients with central nervous system (CNS) metastasis, prognosis is particularly poor. We recently demonstrated a novel route of ALL CNS metastasis dependent on PI3Kδ regulation of the laminin receptor integrin α6. B-ALL cells did not, however, rely on PI3Kδ signaling for growth. Here we show that broad targeting of PI3K isoforms can induce growth arrest in B-ALL, reducing systemic disease burden in mice treated with a single agent pan-PI3Ki, copanlisib. Moreover, we show that cellular stress activates PI3K/Akt-dependent survival pathways in B-ALL, exposing their vulnerability to PI3Kδ and pan-PI3Ki. The addition of a brief course of copanlisib to chemotherapy delivered the combined benefits of increased survival, decreased systemic disease, and reduced CNS metastasis. These data suggest the promising, multifaceted potential of pan-PI3Ki for B-ALL CNS prophylaxis, systemic disease control, and chemosensitization.
Keywords: CNS relapse; PI3K inhibition; acute lymphoblastic leukemia; chemosensitization; microenvironment.