Molecular insight into the T798M gatekeeper mutation-caused acquired resistance to tyrosine kinase inhibitors in ErbB2-positive breast cancer

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) accounts for about 20% to 30% of all BC subtypes and is characterized by invasive disease and poor prognosis. With the emergence of anti-HER2 target drugs, HER2-positive BC patient outcomes have changed dramatically. However, treatment failure is mostly due to drug resistance and the special treatment needs of different subgroups. Small molecule tyrosine kinase inhibitors can inhibit multiple targets of the human epidermal growth factor receptor family and activate PI3K/AKT, MAPK, PLC γ, ERK1/2, JAK/STAT, and other pathways affecting the expression of MDM2, mTOR, p27, and other transcription factors. This can help regulate the differentiation, apoptosis, migration, growth, and adhesion of normal cells and reverse drug resistance to a certain extent. These inhibitors can cross the blood-brain barrier and be administered orally. They have a good synergistic effect with effective drugs such as trastuzumab, pertuzumab, t-dm1, and cyclin-dependent kinase 4 and 6 inhibitors. These advantages have resulted in small-molecule tyrosine kinase inhibitors attracting attention. The new small-molecule tyrosine kinase inhibitor was investigated in multi-target anti-HER2 therapy, showed a good effect in preclinical and clinical trials, and to some extent, improved the prognosis of HER2-positive BC patients. Its use could lead to a de-escalation of treatment in some patients, possibly preventing unnecessary procedures along with the associated side effects and costs.

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Recent Updates on the Therapeutic Potential of HER2 Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer

Current Cancer Drug Targets ◽

10.2174/1568009617666170623122213 ◽

2018 ◽

Vol 18 (4) ◽

pp. 306-327 ◽

Cited By ~ 11

Author(s):

Heena Singla ◽

Anjana Munshi ◽

Raja Paramjit Singh Banipal ◽

Vinod Kumar

Keyword(s):

Breast Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Kinase Inhibitors ◽

Therapeutic Potential ◽

Her2 Receptor ◽

Her2 Positive ◽

Her2 Positive Breast Cancer ◽

Development Of Resistance ◽

Positive Breast Cancer

HER2 positive breast cancer is characterized by the low survival rate in the metastatic patients. Development of resistance and disease-relapse are the major problems associated with the currently available therapies for HER2 positive breast cancer. There are two major targeted therapies for HER2 positive breast cancer viz. monoclonal antibodies and tyrosine-kinase inhibitors, and both of these therapies have their advantages and limitations. To address the limitations associated with the existing therapies, use of antibodies and TKIs as combination therapy proved to be more effective. Various chemical modifications can be performed on tyrosine-kinase inhibitors to develop novel ligands with increased selectivity for HER2 kinase. A number of tyrosine-kinase inhibitors are in various phases of clinical trials for the treatment of HER2 positive breast cancer. In the current review article, recent developments on various HER2 tyrosine-kinase inhibitors have been reported. Various structurally different scaffolds bind to the HER2 receptor and exhibit potent anti-cancer activities. The structural and pharmacophoric requirements of the scaffolds are discussed in detail so as to discover effective drug candidates for the treatment of HER2 positive breast cancer.

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Beyond Trastuzumab: Small Molecule Tyrosine Kinase Inhibitors in HER‐2–Positive Breast Cancer

The Oncologist ◽

10.1634/theoncologist.2009-0142 ◽

2009 ◽

Vol 14 (11) ◽

pp. 1061-1069 ◽

Cited By ~ 41

Author(s):

Vivek Roy ◽

Edith A. Perez

Keyword(s):

Breast Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Small Molecule ◽

Kinase Inhibitors ◽

Her 2 ◽

Positive Breast Cancer

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Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells

Investigational New Drugs ◽

10.1007/s10637-010-9415-5 ◽

2010 ◽

Vol 29 (5) ◽

pp. 752-759 ◽

Cited By ~ 31

Author(s):

Norma O’Donovan ◽

Annette T. Byrne ◽

Aisling E. O’Connor ◽

Sharon McGee ◽

William M. Gallagher ◽

...

Keyword(s):

Breast Cancer ◽

Tyrosine Kinase ◽

Cancer Cells ◽

Tyrosine Kinase Inhibitors ◽

Breast Cancer Cells ◽

Kinase Inhibitors ◽

Synergistic Interaction ◽

Her 2 ◽

Positive Breast Cancer

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

Carcinogenesis ◽

10.1093/carcin/bgy192 ◽

2018 ◽

Vol 40 (8) ◽

pp. 998-1009 ◽

Cited By ~ 5

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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