Osimertinib is a third-generation
epidermal growth factor receptor and
tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of
lung adenocarcinoma patients harboring EGFR mutations. However, acquired resistance to this targeted
therapy is inevitable, leading to disease relapse within a few years. Therefore, understanding the molecular mechanisms of
osimertinib resistance and identifying novel targets to overcome such resistance are unmet needs of
cancer patients. Here, we investigated the efficacy of two novel CDK12/13 inhibitors, AU-15506 and AU-16770, in
osimertinib-resistant EGFR mutant
lung adenocarcinoma cells in culture and xenograft models in vivo. We demonstrate that these drugs, either alone or in combination with
osimertinib, are potent inhibitors of
osimertinib-resistant as well as -sensitive
lung adenocarcinoma cells in culture. Interestingly, only the CDK12/13 inhibitor in combination with
osimertinib, although not as monotherapy, suppresses the growth of resistant
tumors in xenograft models in vivo. Taken together, the results of this study suggest that inhibition of CDK12/13 in combination with
osimertinib has the potential to overcome
osimertinib resistance in EGFR mutant
lung adenocarcinoma patients.