Chk1 Inhibition Restores Inotuzumab Ozogamicin Citotoxicity in CD22-Positive Cells Expressing Mutant p53.

ABSTRACT: Inotuzumab ozogamicin (IO) is an anti-CD22 calicheamicin immunoconjugate that has been recently approved for the treatment of relapsed or refractory B-Acute Lymphoblastic Leukemia (r/r B-ALL). We employed both immortalized and primary cells derived from CD22-positive lymphoproliferative disorders to investigate the signaling pathways contributing to IO sensitivity or resistance. We found that the drug reduced the proliferation rate of CD22-positive cell lines expressing wild-type p53, but was remarkably less effective on cells exhibiting mutant p53. In addition, CD22-positive cells surviving IO were mostly blocked in the G2/M phase of the cell cycle because of Chk1 activation that, in the presence of a wild-type p53 background, led to p21 induction. When we combined IO with the Chk1 inhibi

SUBMITTER: Tirro E 

PROVIDER: S-EPMC6387953 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature