Abstract
Tyrosine kinase inhibitors for epidermal growth factor receptor (EGFR TKIs) greatly improved clinical outcomes of patients with non-small cell lung cancer (NSCLC). Unfortunately, primary and acquired resistance limits their clinical benefits. To overcome such resistance, new generations of EGFR TKIs have been developed by targeting newly identified mutations in EGFR. However, much less effort has been put into alternative strategies, such as targeting the intrinsic protective responses to EGFR TKIs. In this study, we found that EGFR TKIs, including gefitinib and AZD9291, impaired lysosome-dependent degradation of SQSTM1, thus compromising their anti-cancer efficiency. By accumulating in the lysosome lumen, gefitinib and AZD9291 attenuated lysosomal acidification and impaired autolysosomal degradation of SQSTM1 owing to their intrinsic alkalinity. As a result, SQSTM1 protein was stabilized in response to gefitinib and AZD9291 treatment and conferred EGFR TKI resistance. Depleting SQSTM1 significantly increased the sensitivity of NSCLC cells to gefitinib and AZD9291 both in vitro and in vivo. Furthermore, a chemically modified gefitinib analog lacking alkalinity displayed stronger inhibitory effects on NSCLC cells. Therefore, targeting accumulated SQSTM1 or chemically modified EGFR TKIs may represent new strategies to increase the effectiveness of EGFR targeted therapy.
Highlights
IntroductionLung cancer is the most frequent cause of cancer-associated death worldwide, and nonsmall cell lung cancer (NSCLC) (non-small cell lung cancer) accounts for 80% of lung cancers.[1] NSCLC patients initially respond to chemotherapy, the duration of the response is often limited, and NSCLC patients with multiple relapses are generally resistant to chemotherapy
Lung cancer is the most frequent cause of cancer-associated death worldwide, and nonsmall cell lung cancer (NSCLC) accounts for 80% of lung cancers.[1]
NSCLC patients initially respond to chemotherapy, the duration of the response is often limited, and NSCLC patients with multiple relapses are generally resistant to chemotherapy
Summary
Lung cancer is the most frequent cause of cancer-associated death worldwide, and NSCLC (non-small cell lung cancer) accounts for 80% of lung cancers.[1] NSCLC patients initially respond to chemotherapy, the duration of the response is often limited, and NSCLC patients with multiple relapses are generally resistant to chemotherapy. TKIs (tyrosine kinase inhibitors) of EGFR (epidermal growth factor receptor) have been accepted as the first-line treatment option for NSCLC patients with mutant EGFR.[2] almost all NSCLC patients who originally respond to EGFR TKI treatment eventually experience disease progression due to acquired resistance, resulting in a limited 5-year survival rate of NSCLC patients that ranges from 4 to 17%.3. Alternative strategies are urgently needed to overcome TKI resistance
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