Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy

Abstract

TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDAapproved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified 27 cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null hESC in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively resensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the resensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Moreover, we confirmed that targeting ZNF207/BuGZ sensitizes p53-null hESC to cisplatin. These data indicate that targeted inhibition of spindle assembly checkpoints (SAC) and chromosomal organizing centers may provide a way to treat p53-deficient cancer cells with standard chemotherapy drugs. Development of small-molecule inhibitors of SAC proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53mutant cancers. Significance: These findings show that inhibition of spindle assembly checkpoints and chromosomal organizing centers may provide a new way to treat p53-deficient cancer cells with standard chemotherapy drugs.

Genome Instability and Pressure on Non-Homologous end Joining drives Chemotherapy Resistance via a DNA Repair Crisis Switch in Triple Negative Breast Cancer.

“…Almost all TNBC harbor TP53 mutations, with 82% of patients displaying somatic alterations (6). Most TP53 mutations confer resistance to drugs that directly target DNA or DNA synthesis (27). In our study, the lines that achieved the highest levels of resistance, MDA-MB-231 and BT549, have R280K and R249S p53 gain-of-function missense mutations, respectively.…”

Dual-functional significance of ATM-mediated phosphorylation of spindle assembly checkpoint component Bub3 in mitosis and the DNA damage response

“…These mutations may affect the phosphorylation of Bub3. Given that the inhibition of SAC protein activities sensitizes cancer cells to chemotherapy and radiotherapy ( 35 , 36 , 37 ), our findings on the dual function of ATM phosphorylation make it a plausible target for radiosensitization and chemosensitization.…”

MiR-9-3p regulates the biological functions and drug resistance of gemcitabine-treated breast cancer cells and affects tumor growth through targeting MTDH

“…VEGF is a growth factor specifically acting on vascular endothelial cells, and plays an important role in the formation of tumor neovascularization [ 31 ]. P53 gene is a tumor suppressor gene with the highest mutation frequency in tumors, and cells with deletion or mutation of P53 show resistance to chemotherapy drugs [ 32 ]. EMT, which is a major characteristic of invasive tumor cells, is characterized by decreased E-Cadherin expression and increased N-Cadherin expression [ 33 ].…”