Model for the effects of the PI3K-δ inhibitor idelalisib and the IGF1R inhibitor linsitinib on PI3K-δ inhibitor–sensitive and –resistant CLL cells. (A) PI3K-δ is activated by the B-cell receptor (Ag, antigen) and inhibited by idelalisib, thus ablating the PI3K pathway-mediated growth and survival program that activates AKT signaling, which is required for CLL cell survival. (B) Upregulation of IGF1R expression via GSK3 and FOXO1 activates the MAPK pathway-mediated growth and survival program, thus leading to CLL cell survival. It is not known what leads to the activation of GSK3 and FOXO1 in PI3K-δ inhibitor–resistant CLL cells; however, FOXO1 activation is normally inhibited by AKT signaling downstream of the PI3K pathway. (C) Inhibition of IGF1R by linsitinib abolishes the MAPK-mediated growth and survival program, causing cell death in PI3K-δ–resistant CLL cells. The simultaneous inhibition of PI3K-δ is required because reactivation of PI3K/AKT signaling leads to FOXO1 inhibition and failure to upregulate IGF1R. In the serial-adoptive transfer and treatment experiments, Scheffold et al used the specific PI3K-δ inhibitor GS-649443 (rather than idelalisib) because this has favorable pharmacokinetic properties in mice.