Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.

Sangai, Takafumi; Akçakanat, Argun; Chen, Huiqin; Tarco, Emily; Wu, Yun; Do, Kim‐Anh; Miller, Todd W.; Arteaga, Carlos L.; Mills, Gordon B.; González-Angulo, Ana M.; Meric‐Bernstam, Funda

doi:10.1200/jco.2012.30.15_suppl.1054

Cited by 14 publications

(14 citation statements)

References 36 publications

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“…12 The antitumor activity of MK-2206 is greater in some, but not all, breast cancer cell lines with PTEN loss or PIK3CA mutation. 50 Our data show that the sensitivity of MK-2206 in DLBCL cell lines correlated with AKT activation status, suggesting the on-target effect of MK-2206 in DLBCL cells. Interestingly, DOHH2 cells (GCB-DLBCL with MYC/BCL2 rearrangements and wild-type p53) and LP (ABC-DLBCL with mutated p53) cells demonstrated high MK-2206 sensitivity.…”

Section: Discussionmentioning

confidence: 50%

AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma

Wang

Xu-Monette

Jabbar

et al. 2017

The American Journal of Pathology

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AKT signaling is important for proliferation and survival of tumor cells. The clinical significance of AKT activation in diffuse large B-cell lymphoma (DLBCL) is not well analyzed. Here, we assessed expression of phosphorylated AKT (p-AKT) in 522 DLBCL patients. We found that high levels of p-AKT nuclear expression, observed in 24.3% of the study cohort, were associated with significantly worse progression-free survival and Myc and Bcl-2 overexpression. However, multivariate analysis indicated that AKT hyperactivation was not an independent factor. miRNA profiling analysis demonstrated that 63 miRNAs directly or indirectly related to the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway were differentially expressed between DLBCLs with high and low p-AKT nuclear expression. We further targeted AKT signaling using a highly selective AKT inhibitor MK-2206 in 26 representative DLBCL cell lines and delineated signaling alterations using a reverse-phase protein array. MK-2206 treatment inhibited lymphoma cell viability, and MK-2206 sensitivity correlated with AKT activation status in DLBCL cells. On MK-2206 treatment, p-AKT levels and downstream targets of AKT signaling were significantly decreased, likely because of the decreased feedback repression; Rictor and phosphatidylinositol 3-kinase expression and other compensatory pathways were also induced. This study demonstrates the clinical and therapeutic implications of AKT hyperactivation in DLBCL and suggests that AKT inhibitors need to be combined with other targeted agents for DLBCL to achieve optimal clinical efficacy.

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Section: Discussionmentioning

confidence: 50%

AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma

Wang

Xu-Monette

Jabbar

et al. 2017

The American Journal of Pathology

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“…The relevance of combining everolimus and endocrine therapy in patients displaying resistance to nonsteroidal AIs is supported by data from two recent randomized clinical trials indicating the benefit of such a combination on clinical outcome . Finally, the MK‐2206 has recently been shown to act synergistically with several therapeutic agents used in breast cancer …”

Section: Discussionmentioning

confidence: 98%

Molecular characterization of anastrozole resistance in breast cancer: Pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK‐2206 with an aromatase inhibitor

Vilquin

Villedieu

Grisard

et al. 2013

Intl Journal of Cancer

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Acquisition of resistance to aromatase inhibitors (AIs) remains a major drawback in the treatment of estrogen receptor alpha (ERa)-positive breast cancers. The Res-Ana cells, a new model of acquired resistance to anastrozole, were established by longterm exposure of aromatase-overexpressing MCF-7 cells to this drug. These resistant cells developed ER-independent mechanisms of resistance and decreased sensitivity to the AI letrozole or to ERa antagonists. They also displayed a constitutive activation of the PI3K=Akt=mTOR pathway and a deregulated expression of several ErbB receptors. An observed increase in the phospho-Akt=Akt ratio between primary and matched recurrent breast tumors of patients who relapsed under anastrozole adjuvant therapy also argued for a pivotal role of the Akt pathway in acquired resistance to anastrozole. Ectopic overexpression of constitutively active Akt1 in control cells was sufficient to induce de novo resistance to anastrozole. Strikingly, combining anastrozole with the highly selective and allosteric Akt inhibitor MK-2206 or with the mTOR inhibitor rapamycin increased sensitivity to this AI in the control cells and was sufficient to overcome resistance and restore sensitivity to endocrine therapy in the resistant cells. Our findings lead to us proposing a model of anastrozole-acquired resistance based on the selection of cancer-initiating-like cells possessing self-renewing properties, intrinsic resistance to anastrozole and sensitivity to MK-2206. Altogether, our work demonstrated that the Akt=mTOR pathway plays a key role in resistance to anastrozole and that combining anastrozole with Akt=mTOR pathway inhibitors represents a promising strategy in the clinical management of hormone-dependent breast cancer patients.In 60% of premenopausal patients and 75% of postmenopausal patients, breast cancer is a hormone-dependent disease that relies on the mitogenic effects of estrogen to drive carcinogenesis. Aromatase inhibitors (AIs) are now considered to be the standard of care for postmenopausal patients with estrogen receptor alpha (ERa)-positive (ER1) breast cancer as they have proven to be more effective than the selective estrogen receptor modulator tamoxifen (Tam). 1 Despite the proven clinical efficacy of AIs, de novo and acquired resistance still occurs and constitutes a major impediment to successful therapy.The mechanisms involved in resistance to AIs remain poorly described and few cellular models mimicking resistance to AIs are currently available. Aromatase-transfected and longterm estrogen-deprived (LTED) cell lines have been proposed as cellular models of resistance to AIs, based on the hypothesis that lack of hormone in the environment could mimic the withdrawal of estrogen that occurs during treatment with AIs. 2,3 However, several studies suggest that the molecular events taking place during estrogen deprivation may differ from those occurring during AI exposure. 2-4 Thus, cellular Key words: breast cancer, endocrine therapy, anastrozole resistance, Akt=mTOR pathway, sig...

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“…These mechanistic insights may contribute towards a retooling of current chemotherapeutic regimens, or in establishing novel trials with rapamycin and molecular-targeted agents that act specifically on proteins such as Akt. 18 We highlight the potential of nanotherapeutics for enabling preferential and simultaneous delivery of specific combinations of synergistic drugs. Synergy was ratio specific, with more pronounced antitumor effects observed in ratios containing less paclitaxel than rapamycin.…”

Section: Discussionmentioning

confidence: 99%

“…Paclitaxel had a nominal impact on growth inhibition at lower doses, proving highly efficacious only at higher doses in both free and nanoparticle form. Given that MDA-MB-468 and MCF-7 cells were rapamycin-sensitive, 5,9,18 rapamycin and combination nanoparticles proved more effective at inhibiting breast cancer cell growth compared to paclitaxel nanoparticles alone at low doses. At the 10 ng/ml dose of rapamycin (3.3 ng/ml paclitaxel), combination nanoparticles were much more effective at inhibiting cell growth than single loaded nanoparticles (P < 0.001) in both cell lines, highlighting drug synergy at higher combination doses.…”

Section: Drug-containing Nanoparticles Synergistically Inhibit Breastmentioning

confidence: 99%

Colocalized Delivery of Rapamycin and Paclitaxel to Tumors Enhances Synergistic Targeting of the PI3K/Akt/mTOR Pathway

Blanco

Sangai

et al. 2014

Molecular Therapy

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Ongoing clinical trials target the aberrant PI3K/Akt/mammalian target of rapamycin (mTOR) pathway in breast cancer through administration of rapamycin, an allosteric mTOR inhibitor, in combination with paclitaxel. However, synergy may not be fully exploited clinically because of distinct pharmacokinetic parameters of drugs. This study explores the synergistic potential of site-specific, colocalized delivery of rapamycin and paclitaxel through nanoparticle incorporation. Nanoparticle drug loading was accurately controlled, and synergistic drug ratios established in vitro. Precise drug ratios were maintained in tumors 48 hours after nanoparticle administration to mice, at levels twofold greater than liver and spleen, yielding superior antitumor activity compared to controls. Simultaneous and preferential in vivo delivery of rapamycin and paclitaxel to tumors yielded mechanistic insights into synergy involving suppression of feedback loop Akt phosphorylation and its downstream targets. Findings demonstrate that a same time, same place, and specific amount approach to combination chemotherapy by means of nanoparticle delivery has the potential to successfully translate in vitro synergistic findings in vivo. Predictive in vitro models can be used to determine optimum drug ratios for antitumor efficacy, while nanoparticle delivery of combination chemotherapies in preclinical animal models may lead to enhanced understanding of mechanisms of synergy, ultimately opening several avenues for personalized therapy.

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Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.

Cited by 14 publications

References 36 publications

AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma

AKT Hyperactivation and the Potential of AKT-Targeted Therapy in Diffuse Large B-Cell Lymphoma

Molecular characterization of anastrozole resistance in breast cancer: Pivotal role of the Akt/mTOR pathway in the emergence of de novo or acquired resistance and importance of combining the allosteric Akt inhibitor MK‐2206 with an aromatase inhibitor

Colocalized Delivery of Rapamycin and Paclitaxel to Tumors Enhances Synergistic Targeting of the PI3K/Akt/mTOR Pathway

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