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Jean Louis Pujol
OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 1
- Now Available
OA08.05 - Notch Inhibition Overcomes Resistance to Tyrosine Kinase Inhibitors Promoted by Gate-Keeper Mutations in EGFR-Driven Lung Adenocarcinoma (Now Available) (ID 639)
11:00 - 12:30 | Author(s): Jean Louis Pujol
EGFR mutated lung adenocarcinoma patients treated with gefitinib and osimertinib showed a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It has been generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, indicating that the use of single drug to treat efficiently EGFR-driven lung adenocarcinoma might have limited value while a strategy based on combinational drug therapy could be more effective at mitigating the effects of gatekeeper mutations.Method
We have combined the use of EGFR-driven genetic engineered mouse models and patient-derived xenografts, adenocarcinoma cell lines and primary samples from EGFR mutated patients.Result
We uncover here that gefitinib and osimertinib increase STAT3 phosphorylation (pSTAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induces a pSTAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we show that tyrosine kinase inhibitor resistant tumors, with EGFRT790M and EGFRC797S mutations, are highly responsive to the combined treatment of Notch inhibitors with gefitinib and osimertinib respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increase during relapse and correlate with shorter progression-free survival.Conclusion
Our results show that the Notch pathway plays a major role in the relapse of lung adenocarcinoma patients treated with EGFR TKIs, providing a rationale to treat patients that become resistant to EGFR TKI with a combination of the same TKI and Notch inhibitors.
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