| HRA002758
(Controlled Access)
|
to identify the key regulators of EGFR-TKI sensitivity or resistance, we constructed EGFR-TKI-sensitive and -resistant LUAD patient-derived xenografts (PDXs), and analyzed gene mutation changes among them. Using this strategy, we found an increased frequency of L12_16 amino acid deletion mutation in the signaling peptide region of NOTCH4 (NOTCH4delL12_16) among EGFR-TKI-sensitive PDXs in comparison to these in EGFR-TKI-resistant PDXs. A similar pattern of increased NOTCH4delL12_16 was also observed in EGFR-TKI-sensitive compared to those in EGFR-TKI-resistant LUAD patients. Functionally, exogenous induction of NOTCH4delL12_16 in EGFR-TKI-resistant LUAD cells sensitized them to EGFR-TKIs, and this process is mainly mediated by the reduction of intracellular domain fragment of NOTCH4 (NICD4) caused by the disruption of NOTCH4 translocation from cytosol to plasma membrane due to NOTCH4delL12_16 mutation. |
