Pan-PI3Ki targets multiple B-ALL microenvironment interactions that fuel systemic and CNS relapse

Abstract

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

Ackowledgements

We thank Zhiguo Li and Kevin Brennan for consultation on statistical analysis. Figure 6(J) schematic created with BioRender.

Disclosure statement

We are reporting that we have received the drug, GS-649443, from Gilead Sciences, Inc.

Data availability statement

Please contact the corresponding author for original data and protocols.

Additional information

Funding

This work was supported by the Error! Hyperlink reference not valid. and by NIH/NCI R01-CA234580. GS-649443 was provided by Stacey Tannheimer at Gilead Sciences, Inc.