scholarly journals Dual Inhibition of AKT and MEK Pathways Potentiates the Anti-Cancer Effect of Gefitinib in Triple-Negative Breast Cancer Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1205
Author(s):  
Kyu Sic You ◽  
Yong Weon Yi ◽  
Jeonghee Cho ◽  
Yeon-Sun Seong
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Protein Kinase Inhibitors ◽  
Akt Inhibitor ◽  
Term Survival ◽  
Viral Oncogene ◽  
Dual Inhibition ◽  
Viral Oncogene Homolog

There is an unmet medical need for the development of new targeted therapeutic strategies for triple-negative breast cancer (TNBC). With drug combination screenings, we found that the triple combination of the protein kinase inhibitors (PKIs) of the epidermal growth factor receptor (EGFR), v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK) is effective in inducing apoptosis in TNBC cells. A set of PKIs were first screened in combination with gefitinib in the TNBC cell line, MDA-MB-231. The AKT inhibitor, AT7867, was identified and further analyzed in two mesenchymal stem-like (MSL) subtype TNBC cells, MDA-MB-231 and HS578T. A combination of gefitinib and AT7867 reduced the proliferation and long-term survival of MSL TNBC cells. However, gefitinib and AT7867 induced the activation of the rat sarcoma (RAS)/ v-raf-1 murine leukemia viral oncogene homolog (RAF)/MEK/ extracellular signal-regulated kinase (ERK) pathway. To inhibit this pathway, MEK/ERK inhibitors were further screened in MDA-MB-231 cells in the presence of gefitinib and AT7867. As a result, we identified that the MEK inhibitor, PD-0325901, further enhanced the anti-proliferative and anti-clonogenic effects of gefitinib and AT7867 by inducing apoptosis. Our results suggest that the dual inhibition of the AKT and MEK pathways is a novel potential therapeutic strategy for targeting EGFR in TNBC cells.

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

Abstract B178: Targeting Myc in triple-negative breast cancer models through the dual inhibition of PIM kinases and CDK9

2018 ◽  
Author(s):  
Hillary Haws ◽  
Wontak Kim ◽  
Adam Siddiqui-Jain ◽  
David J. Bearss ◽  
Steven L. Warner ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pim Kinases ◽  
Cancer Models ◽  
Dual Inhibition

scholarly journals Diverse Roles of Annexin A6 in Triple-Negative Breast Cancer Diagnosis, Prognosis and EGFR-Targeted Therapies

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1855 ◽  
Author(s):  
Olga Y. Korolkova ◽  
Sarrah E. Widatalla ◽  
Stephen D. Williams ◽  
Diva S. Whalen ◽  
Heather K. Beasley ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Triple Negative Breast Cancer ◽  
Kinase Inhibitors ◽  
Triple Negative ◽  
Acquired Resistance ◽  
Breast Cancer Diagnosis ◽  
Scaffolding Protein ◽  
Poor Overall Survival ◽  
Suppressor Activity

The calcium (Ca2+)-dependent membrane-binding Annexin A6 (AnxA6), is a multifunctional, predominantly intracellular scaffolding protein, now known to play relevant roles in different cancer types through diverse, often cell-type-specific mechanisms. AnxA6 is differentially expressed in various stages/subtypes of several cancers, and its expression in certain tumor cells is also induced by a variety of pharmacological drugs. Together with the secretion of AnxA6 as a component of extracellular vesicles, this suggests that AnxA6 mediates distinct tumor progression patterns via extracellular and/or intracellular activities. Although it lacks enzymatic activity, some of the AnxA6-mediated functions involving membrane, nucleotide and cholesterol binding as well as the scaffolding of specific proteins or multifactorial protein complexes, suggest its potential utility in the diagnosis, prognosis and therapeutic strategies for various cancers. In breast cancer, the low AnxA6 expression levels in the more aggressive basal-like triple-negative breast cancer (TNBC) subtype correlate with its tumor suppressor activity and the poor overall survival of basal-like TNBC patients. In this review, we highlight the potential tumor suppressor function of AnxA6 in TNBC progression and metastasis, the relevance of AnxA6 in the diagnosis and prognosis of several cancers and discuss the concept of therapy-induced expression of AnxA6 as a novel mechanism for acquired resistance of TNBC to tyrosine kinase inhibitors.

Learning from every patient: Real-world clinical outcomes of patients with metastatic triple-negative breast cancer treated in the community oncology setting.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12554-e12554
Author(s):  
Anchit Khanna ◽  
Elani Bowers ◽  
Amin Haiderali ◽  
Michael Marian Slancar ◽  
Natalie Heather Rainey ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcomes ◽  
Triple Negative Breast Cancer ◽  
Real World ◽  
Index Date ◽  
Triple Negative ◽  
Single Agent ◽  
Treatment Patterns ◽  
Duration Of Treatment ◽  
Term Survival

e12554 Background: Triple-negative breast cancer is a biologically aggressive disease that accounts for 15% of all breast cancers, of which around 4-5% are metastatic (mTNBC) at diagnosis. Notably, there is no standard of care for mTNBC in the first line (1L) setting. This, in addition to higher relapse rates and poor long-term survival, warrants evaluation of real-world treatment patterns, especially in the 1L setting, to better inform on clinical outcomes. Methods: This observational, retrospective, chart review study included a cohort of twenty-six mTNBC patients from six different sites Australia, who commenced 1L treatment between July 1, 2012 and June 30, 2015. Medical records of eligible patients were abstracted using electronic case report forms after gaining relevant ethics approvals. Data on treatment patterns and clinical outcomes in the 1L setting were then collected from the index date until the end of data abstraction or death. The index date is defined as the date of initiation of 1L systemic therapy for mTNBC. Results: In the 1L setting, patients that received combination (52%) chemotherapy was slightly higher than single-agent (48%) chemotherapy. The commonest combination used was Carboplatin-Gemcitabine (12%), and the most common monotherapy was Nab-Paclitaxel (24%). The overall response rate and disease control rate were estimated to be 32% and 60% in the 1L setting. The median duration of treatment and the median time to next line of therapy were calculated to be 98 days and 12.45 (95% CI 2.79, 20.30) months respectively. Importantly, the median progression free survival (sensitivity analysis) and the median overall survival were estimated to be 3.17 (95% CI 1.91, 5.09) and 10.41 (95% CI 5.36, 16.53) months respectively. Conclusions: Chemotherapy is currently the mainstay of treatment for mTNBC. However, disease progression and chemo-related toxicities warrant stratified use of more efficacious and tolerable treatment options, especially in the 1L setting. Results from this study could be useful in comparing the efficacy and cost effectiveness of these emerging targeted and immuno-therapies outside the clinical trial setting.

Efficacy and safety of intensified platinum-based neoadjuvant chemotherapy in locally advanced triple-negative breast cancer: Preliminary results of non-randomized phase II study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12116-e12116 ◽  
Author(s):  
Elena Glazkova ◽  
Mona Frolova ◽  
Marina Stenina ◽  
Ekaterina Ignatova ◽  
Alexey Rumyantsev ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Surgical Treatment ◽  
Phase Ii ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Phase Ii Study ◽  
Brca1 Mutation ◽  
Locally Advanced ◽  
Common Mutation ◽  
Term Survival

e12116 Background: patients with locally-advanced triple negative breast cancer (TNBC) have dismal prognosis with current standard of care therapy. Pathologic complete response (pCR) is the most important prognostic factor for long-term survival of these patients. Methods: this was non-randomized prospective single-center phase II study. Key inclusion criteria were histologically verified locally advanced TNBC, non-eligibility for primary surgical treatment (ie, TNM stage Т2-4N 2-3M0) and no evidence of metastatic disease. Patients were treated with 8 cycles of neoadjuvant doxorubicine, paclitaxel and cisplatin chemotherapy (ATP; doxorubicine 40 mg/m2 day 1, paclitaxel 160 mg/m2 day 1 and cisplatin 50 mg/m2 day 1 every two weeks) with G-CSF support (filgrastim 5 mcg/kg day 2-6). After 8 cycles of chemotherapy patients were referred for surgical treatment; adjuvant radiation therapy was prescribed to all patients. Primary end point was pCR assessed in modified intention-to-treat population (ie, in patients who underwent surgical treatment). Key secondary endpoints were disease-free survival (DFS) and pCR rate according to BRCA status. Results: we enrolled 80 patients, 79 (98.7%) of them underwent surgical treatment and were included in the analysis. Median age was 46 years (25-68), 22 (27.1%) patients had BRCA1 mutations, 5382insC was the most common mutation (17 [77.2%] of patients); 1 (1.2%) patient had CHEK2 mutation. pCR was achieved in 51 (64.5%) patients. In with BRCA1-mutation carriers pCR rate was 61.9%, in patients with 5382insC – 81.2%. 2-year DFS was 77.3%; 2-year overall survival was 91.0% . Most common grade 3-4 adverse events were anemia (29.3%), neutropenia (17.8%), neuropathy (4.9%), stomatitis (3.7%) and thrombocytopenia (1.8%). Conclusions: the ATP regimen was effective in treatment of locally-advanced TNBC, especially in patients with founder 5382insC BRCA1 mutation for Slavic population and deserves further investigation.

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