PI3K inhibitors and the search for the Holy Grail

Abstract

In this issue of Blood, Phillips et al demonstrate an exciting approach to improve efficacy and decrease the toxicity of phosphatidylinositol 3-kinase (PI3K) inhibitors.1 In the past decade, we have learned of the pivotal role PI3K plays in the growth and survival of many cancers, including B-cell malignancies. PI3Ks are also important in the microenvironment, where they have effects on recruitment and differentiation of cells that support the survival of the malignant B cells. There are 4 isoforms: a, b, d, and ϒ. The expression of these isoforms varies by tissue. Preclinical models suggested that specifically inhibiting the d isoform might provide significant efficacy in B-cell malignancies while decreasing potential toxicities of pan inhibitors because its expression is restricted to leukocytes. However, autoimmune problems, particularly colitis, were also seen in these preclinical models.2 There are now 2 PI3K inhibitors that have received regulatory approval for the treatment of B-cell malignancies in the United States. The first was idelalisib, a PI3K d isoform-specific inhibitor. The clinical results of idelalisib are very much in line with what one would have predicted from the preclinical studies, substantial efficacy in lymphoma and chronic lymphocytic leukemia, but also with the colitis, as seen in the mouse models. Liver toxicity has also been observed, which appears to be immune mediated.3