scholarly journals Anti-EGFR monoclonal antibodies and EGFR tyrosine kinase inhibitors as combination therapy for triple-negative breast cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (45) ◽  
pp. 73618-73637 ◽  
Author(s):  
Abderrahim El Guerrab ◽  
Mahchid Bamdad ◽  
Fabrice Kwiatkowski ◽  
Yves-Jean Bignon ◽  
Frédérique Penault-Llorca ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Monoclonal Antibodies ◽  
Combination Therapy ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Triple Negative Breast Cancer ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors

scholarly journals Lapatinib-induced annexin A6 upregulation as an adaptive response of triple-negative breast cancer cells to EGFR tyrosine kinase inhibitors

2018 ◽  
Vol 40 (8) ◽  
pp. 998-1009 ◽  
Author(s):  
Sarrah E Widatalla ◽  
Olga Y Korolkova ◽  
Diva S Whalen ◽  
J Shawn Goodwin ◽  
Kevin P Williams ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Triple Negative Breast Cancer ◽  
Plasma Membranes ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Cholesterol Depletion ◽  
Late Endosomes

Abstract The epidermal growth factor receptor (EGFR) is a major oncogene in triple-negative breast cancer (TNBC), but the use of EGFR-targeted tyrosine kinase inhibitors (TKI) and therapeutic monoclonal antibodies is associated with poor response and acquired resistance. Understanding the basis for the acquired resistance to these drugs and identifying biomarkers to monitor the ensuing resistance remain a major challenge. We previously showed that reduced expression of annexin A6 (AnxA6), a calcium-dependent membrane-binding tumor suppressor, not only promoted the internalization and degradation of activated EGFR but also sensitized TNBC cells to EGFR-TKIs. Here, we demonstrate that prolong (>3 days) treatment of AnxA6-low TNBC cells with lapatinib led to AnxA6 upregulation and accumulation of cholesterol in late endosomes. Basal extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation was EGFR independent and significantly higher in lapatinib-resistant MDA-MB-468 (LAP-R) cells. These cells were more sensitive to cholesterol depletion than untreated control cells. Inhibition of lapatinib-induced upregulation of AnxA6 by RNA interference (A6sh) or withdrawal lapatinib from LAP-R cells not only reversed the accumulation of cholesterol in late endosomes but also led to enrichment of plasma membranes with cholesterol, restored EGFR-dependent activation of ERK1/2 and sensitized the cells to lapatinib. These data suggest that lapatinib-induced AnxA6 expression and accumulation of cholesterol in late endosomes constitute an adaptive mechanism for EGFR-expressing TNBC cells to overcome prolong treatment with EGFR-targeted TKIs and can be exploited as an option to inhibit and/or monitor the frequently observed acquired resistance to these drugs.

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