Lapatinib as a Dual Tyrosine Kinase Inhibitor Unexpectedly Activates Akt in MDA-MB-231 Triple-Negative Breast Cancer Cells

2020 ◽  
Vol 17 (8) ◽  
pp. 1060-1063 ◽  
Author(s):  
Parham Jabbarzadeh Kaboli ◽  
King-Hwa Ling
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Triple Negative Breast Cancer ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Kinase Inhibitor ◽  
Alternative Pathway ◽  
Tnbc Cell Line ◽  
Oncogenic Protein

Background: MDA-MB-231 is a Triple-Negative Breast Cancer (TNBC) cell line, which is resistant to tyrosine kinase inhibitors, such as lapatinib. Lapatinib is well-recognized as an anti- EGFR and anti-Her2 compound. Here, we report one of the possible explanations for lapatinibresistance in TNBC cells, the most incurable type of breast cancer. Methods: Using western blotting, we have observed that lapatinib-treated cells enhanced activation of Akt, an oncogenic protein activated at downstream of EGFR signaling. Results: Anti-EGFR activity of Lapatinib would be counteracted with sustained activation of Akt. We found lapatinib-resistance in TNBC can be managed by administering Akt inhibitors. Further, lapatinib enhanced PI3K/Akt signaling is an alternative pathway to ensure the viability of MDAMB- 231 cells. There might also be unknown targets for lapatinib, which needs further investigation. Conclusion: This observation opens up a new discussion on overcoming resistance to tyrosine kinase inhibitors, a key challenge in treating TNBC.

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.

scholarly journals RON and MET Co-overexpression Are Significant Pathological Characteristics of Poor Survival and Therapeutic Targets of Tyrosine Kinase Inhibitors in Triple-Negative Breast Cancer

2020 ◽  
Vol 52 (3) ◽  
pp. 973-986 ◽  
Author(s):  
Tian-Hao Weng ◽  
Min-Ya Yao ◽  
Xiang-Ming Xu ◽  
Chen-Yu Hu ◽  
Shu-Hao Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Triple Negative Breast Cancer ◽  
Poor Prognosis ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Therapeutic Targets ◽  
Pathological Characteristics ◽  
Tnbc Cell

Purpose Triple-negative breast cancer (TNBC) is highly malignant and has poor prognosis and a high mortality rate. The lack of effective therapy has spurred our investigation of new targets for treating this malignant cancer. Here, we identified RON (macrophage-stimulating 1 receptor) and MET (MET proto-oncogene, receptor tyrosine kinase) as a prognostic biomarker and therapeutic targets for potential TNBC treatment.Materials and MethodsWe analyzed RON and MET expression in 187 primary TNBC clinical samples with immunohistochemistry. We validated the targeted therapeutic effects of RON and MET in TNBC using three tyrosine kinase inhibitors (TKIs): BMS-777607, INCB28060, and tivantinib. The preclinical therapeutic efficacy of the TKIs was mainly estimated using a TNBC xenograft model.ResultsPatients with TNBC had widespread, abnormal expression of RON and MET. There was RON overexpression, MET overexpression, and RON and MET co-overexpression in 63 (33.7%), 63 (33.7%), and 43 cases (23.0%), respectively, which had poor prognosis and short survival. <i>In vivo</i>, the TKI targeting RON ant MET inhibited the activation of the downstream signaling molecules, inhibited TNBC cell migration and proliferation, and increased TNBC cell apoptosis; in the xenograft model, they significantly inhibited tumor growth and shrank tumor volumes. The TKI targeting RON and Met, such as BMS-777607 and tivantinib, yielded stronger anti-tumor effects than INCB28060.ConclusionRON and MET co-overexpression can be significant pathological characteristics in TNBC for poor prognosis. TKIs targeting RON and MET have stronger drug development potential for treating TNBC.

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