The CHK1 inhibitor Prexasertib is effective against in vitro models of aggressive thyroid carcinomas with defective p53 function

Introduction: Tyrosine kinase inhibitors represent the most effective and long-lasting treatment currently available for aggressive thyroid cancers, but in some patients the response is poor or absent. Recently, we demonstrated that the response to Lenvatinib is associated with alterations in TP53 gene or protein. Aiming to find a novel therapeutic strategy for aggressive thyroid cancers, we investigated in vitro the DNA damage response pathway, where p53 plays a crucial role, and tested its inhibition through synthetic lethality or stress sensitization strategies. Methods: The DNA damage response has been characterized in a panel of p53-defective or proficient thyroid cancer cell lines both at basal level and in response to Doxorubicin, a DNA damaging agent, by western blot, immunofluorescence and MTT-based cell viability assay. We then evaluated the effect of a selective CHK1 kinase inhibitor, Prexasertib, either alone or in combination with Doxorubicin. Cell cycle variations and cell death were evaluated by flow-cytometry. Results: The p53-defective thyroid cancer cells showed a higher degree of genomic instability and, in response to Doxorubicin, activated not only ATM/CHK2 but also ATR/CHK1 to bypass p53 and induce DNA repair. We found that Prexasertib was more effective in p53-defective cells, since it significantly reduced tumor cell proliferation due to replicative failure and cell death. Moreover, Doxorubicin potentiated the Prexasertib effects in p53-defective thyroid cancer cells, yet at the lowest doses. Conclusions: This study unravels the potential of Prexasertib as a novel treatment option for aggressive thyroid cancers p53-defective and poorly responsive to tyrosine kinase inhibitors.