Phosphatidylinositol 3-kinase (PI3Ka)/AKT axis blockade with taselisib or ipatasertib enhances the efficacy of anti-microtubule drugs in human breast cancer cells

被引：26

作者：

Morgillo, Floriana ^{[1
]}

Della Corte, Carminia Maria ^{[1
]}

Diana, Anna ^{[1
]}

di Mauro, Concetta ^{[2
]}

Ciaramella, Vincenza ^{[1
]}

Barra, Giusi ^{[3
]}

Belli, Valentina ^{[1
]}

Franzese, Elisena ^{[1
]}

Bianco, Roberto ^{[2
]}

Maiello, Evaristo ^{[4
]}

De Vita, Ferdinando ^{[1
]}

Ciardiello, Fortunato ^{[1
]}

Orditura, Michele ^{[1
]}

机构：

[1] Univ Campania Luigi Vanvitelli, Dipartimento Internist Clin & Sperimentale F Magr, Oncol Med, Naples, Italy

[2] Univ Napoli Federico II, Dipartimento Med Clin & Chirurgia, Oncol Med, Naples, Italy

[3] Univ Campania Luigi Vanvitelli, Dipartimento Internist Clin & Sperimentale F Magr, Immunol Clin, Naples, Italy

[4] IRCCS Casa Sollievo Sofferenza, Foggia, Italy

来源：

ONCOTARGET | 2017年 / 8卷 / 44期

关键词：

AKT; breast cancer; taselisib; ipatasertib; novel drugs; AKT INHIBITOR GDC-0068; PIK3CA MUTATIONS; RESISTANCE; PATHWAY; GROWTH; PTEN; PI3K; METAANALYSIS; COMBINATION; METASTASIS;

D O I：

10.18632/oncotarget.20385

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: The Phosphatidylinositol 3-kinase (PI3Ks) pathway is commonly altereted in breast cancer patients, but its role is still unclear. Taselisib, a mutant PI3Ka selective inhibitor, and ipatasertib, an AKT inhibitor, are currently under investigation in clinical trials in combination with paclitaxel or hormonal therapies in breast cancer. The aim of this study was to evaluate if PI3K or AKT inhibition can prevent resistance to chemotherapy and potentiate its efficacy. Experimental design: The efficacy of combined treatment of ipatasertib and taselisib plus vinorelbine or paclitaxel or eribulin was evaluated in vitro on human breast cancer cells (with different expression profile of hormonal receptors, HER2, and of PI3Ka mutation) on cell survival by using MTT (3,(4,5-dimethylthiazol-2) 2,5 difeniltetrazolium bromide) and colony forming assays on cell apoptosis by flow-cytometry analysis. We also investigated the effect of combined treatment on downstream intracellular signaling, by western blot analysis, and on metastatic properties, by migration assays. Finally, we analyzed changes in cell cytoskeleton by immunofluorescence. Results: A significant synergism of ipatasertib or taselisib plus anti-microtubule chemotherapy in terms of anti-proliferative, pro-apoptotic and anti-metastatic effect was observed. The combined treatment completely inhibited the activation of proteins downstream of PI3K and MAPK pathways and affected the expression of survivin. Combined treatments completely disorganized the cytoskeleton in human breast cancer cells, with contemporary delocalization of survivin from cytoplasm to nucleus, thus suggesting a potential mechanism for this combination. Conclusions: Targeting PI3K may enhance the efficacy of anti-microtubule drugs in human breast cancer cells.

引用

页码：76479 / 76491

页数：13

共 34 条

[1] PI3K/AKT/mTOR pathway inhibitors: the ideal combination partners for breast cancer therapies? [J].

Abraham, Jame .

EXPERT REVIEW OF ANTICANCER THERAPY, 2015, 15 (01) :51-68

[2] Correlation between progression-free survival and overall survival in metastatic breast cancer patients receiving anthracyclines, taxanes, or targeted therapies: a trial-level meta-analysis [J].

Adunlin, George ;

Cyrus, John W. W. ;

Dranitsaris, George .

BREAST CANCER RESEARCH AND TREATMENT, 2015, 154 (03) :591-608

[3] The emergence of targeted drugs in breast cancer to prevent resistance to endocrine treatment and chemotherapy [J].

Austreid, Eilin ;

Lonning, Per Eystein ;

Eikesdal, Hans Petter .

EXPERT OPINION ON PHARMACOTHERAPY, 2014, 15 (05) :681-700

[4] Cytoskeletal rearrangement and Src and PI-3K-dependent Akt activation control GABABR-mediated chemotaxis [J].

Barati, Michelle T. ;

Lukenbill, Janice ;

Wu, Rui ;

Rane, Madhavi J. ;

Klein, Jon B. .

CELLULAR SIGNALLING, 2015, 27 (06) :1178-1185

[5] Prognosis for Patients With Metastatic Breast Cancer Who Achieve a No-Evidence-of-Disease Status After Systemic or Local Therapy [J].

Bishop, Andrew J. ;

Ensor, Joe ;

Moulder, Stacy L. ;

Shaitelman, Simona F. ;

Edson, Mark A. ;

Whitman, Gary J. ;

Bishnoi, Sandra ;

Hoffman, Karen E. ;

Stauder, Michael C. ;

Valero, Vicente ;

Buchholz, Thomas A. ;

Ueno, Naoto T. ;

Babiera, Gildy ;

Woodward, Wendy A. .

CANCER, 2015, 121 (24) :4324-4332

[6] Phase I/II dose-escalation study of PI3K inhibitors pilaralisib or voxtalisib in combination with letrozole in patients with hormone-receptor-positive and HER2-negative metastatic breast cancer refractory to a non-steroidal aromatase inhibitor [J].

Blackwell, Kimberly ;

Burris, Howard ;

Gomez, Patricia ;

Henry, N. Lynn ;

Isakoff, Steven ;

Campana, Frank ;

Gao, Lei ;

Jiang, Jason ;

Mace, Sandrine ;

Tolaney, Sara M. .

BREAST CANCER RESEARCH AND TREATMENT, 2015, 154 (02) :287-297

[7] Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors [J].

Blake, James F. ;

Xu, Rui ;

Bencsik, Josef R. ;

Xiao, Dengming ;

Kallan, Nicholas C. ;

Schlachter, Stephen ;

Mitchell, Ian S. ;

Spencer, Keith L. ;

Banka, Anna L. ;

Wallace, Eli M. ;

Gloor, Susan L. ;

Martinson, Matthew ;

Woessner, Richard D. ;

Vigers, Guy P. A. ;

Brandhuber, Barbara J. ;

Liang, Jun ;

Safina, Brian S. ;

Li, Jun ;

Zhang, Birong ;

Chabot, Christine ;

Do, Steven ;

Lee, Leslie ;

Oeh, Jason ;

Sampath, Deepak ;

Lee, Brian B. ;

Lin, Kui ;

Liederer, Bianca M. ;

Skelton, Nicholas J. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (18) :8110-8127

[8] 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3) [J].

Cardoso, F. ;

Costa, A. ;

Senkus, E. ;

Aapro, M. ;

Andre, F. ;

Barrios, C. H. ;

Bergh, J. ;

Bhattacharyya, G. ;

Biganzoli, L. ;

Cardoso, M. J. ;

Carey, L. ;

Corneliussen-James, D. ;

Curigliano, G. ;

Dieras, V. ;

El Saghir, N. ;

Eniu, A. ;

Fallowfield, L. ;

Fenech, D. ;

Francis, P. ;

Gelmon, K. ;

Gennari, A. ;

Harbeck, N. ;

Hudis, C. ;

Kaufman, B. ;

Krop, I. ;

Mayer, M. ;

Meijer, H. ;

Mertz, S. ;

Ohno, S. ;

Pagani, O. ;

Papadopoulos, E. ;

Peccatori, F. ;

Pernault-Llorca, F. ;

Piccart, M. J. ;

Pierga, J. Y. ;

Rugo, H. ;

Shockney, L. ;

Sledge, G. ;

Swain, S. ;

Thomssen, C. ;

Tutt, A. ;

Vorobiof, D. ;

Xu, B. ;

Norton, L. ;

Winer, E. .

BREAST, 2017, 31 :244-259

[9] Frequent Mutational Activation of the PI3K-AKT Pathway in Trastuzumab-Resistant Breast Cancer [J].

Chandarlapaty, Sarat ;

Sakr, Rita A. ;

Giri, Dilip ;

Patil, Sujata ;

Heguy, Adriana ;

Morrow, Monica ;

Modi, Shanu ;

Norton, Larry ;

Rosen, Neal ;

Hudis, Clifford ;

King, Tari A. .

CLINICAL CANCER RESEARCH, 2012, 18 (24) :6784-6791

[10] Taxane-containing regimens for metastatic breast cancer [J].

Ghersi, Davina ;

Willson, Melina L. ;

Chan, Matthew Ming Ki ;

Simes, John ;

Donoghue, Emma ;

Wilcken, Nicholas .

COCHRANE DATABASE OF SYSTEMATIC REVIEWS, 2015, (06)

← 1 2 3 4 →