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

• Published in: Frontiers in oncology 2019-02, Vol.9, p.57-57
• Main Authors: Tirrò, Elena, Massimino, Michele, Romano, Chiara, Pennisi, Maria Stella, Stella, Stefania, Vitale, Silvia Rita, Fidilio, Annamaria, Manzella, Livia, Parrinello, Nunziatina Laura, Stagno, Fabio, Palumbo, Giuseppe Alberto, La Cava, Piera, Romano, Alessandra, Di Raimondo, Francesco, Vigneri, Paolo G
• Format: Article
• Language: English
• Subjects: antibody-drug conjugates; B-ALL; Chk1; inotuzumab ozogamicin; Oncology; p53
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2019.00057

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 inhibitor UCN-01, we successfully abrogated IO-induced G2/M arrest regardless of the underlying p53 status, indicating that the DNA damage response triggered by IO is also modulated by p53-independent mechanisms. To establish a predictive value for p53 in determining IO responsiveness, we expressed mutant p53 in cell lines displaying the wild-type gene and observed an increase in IO IC values. Likewise, overexpression of an inducible wild-type p53 in cells natively presenting a mutant protein decreased their IC for IO. These results were also confirmed in primary CD22-positive cells derived from B-ALL patients at diagnosis and from patients with r/r B-ALL. Furthermore, co-treatment with IO and UCN-01 significantly increased cell death in primary cells expressing mutant p53. In summary, our findings suggest that p53 status may represent a biomarker predictive of IO efficacy in patients diagnosed with CD22-positive malignancies.