Novel CDK12/13 Inhibitors AU-15506 and AU-16770 Are Potent Anti-Cancer Agents in EGFR Mutant Lung Adenocarcinoma with and without Osimertinib Resistance.
Tapan K MaityEun Young KimConstance M CultraroAbhilash VenugopalanLeena KhareRamulu PoddutooriSivapriya MarappanSamiulla D SyedWilliam G TelfordSusanta SamajdarMurali RamachandraUdayan GuhaPublished in: Cancers (2023)
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.
Keyphrases
- epidermal growth factor receptor
- advanced non small cell lung cancer
- tyrosine kinase
- small cell lung cancer
- end stage renal disease
- chronic kidney disease
- induced apoptosis
- ejection fraction
- newly diagnosed
- cell cycle
- sensitive detection
- signaling pathway
- prognostic factors
- cell proliferation
- cell cycle arrest
- endoplasmic reticulum stress
- drug induced
- patient reported
- risk assessment
- quantum dots
- mass spectrometry
- visible light
- free survival