Identification of subtypes of triple negative breast cancer (TNBC) that are sensitive to CDK4/6 inhibition.

Asghar, Uzma; Herrera-Abreu, María Teresa; Cutts, Ros; Babina, Irina S.; Pearson, Alex; Turner, Nicholas C.

doi:10.1200/jco.2015.33.15_suppl.11098

Cited by 16 publications

(13 citation statements)

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“…In search for cancer types particularly sensitive to palbociclib, Finn and colleagues demonstrated that luminal-type breast cancer cells expressing oestrogen receptor (called ER+), including luminal-type cells with amplification of the HER2 (ERBB2) receptor (referred to as HER2+), were significantly more sensitive to palbociclib than ER-negative (ER-) breast cancer cells with basal-like histology 139 . Moreover, palbociclib sensitivity was increased upon loss of p16 INK4A , p15 INK4B or E2F1, low cyclin E1 expression or high androgen receptor levels; on the other hand, loss of RB abolished and amplification of the CCNE1 gene or overexpression of E2F2 decreased the sensitivity 132, 140–142 . The effect of CDK4 amplification on CDK4/6 inhibitor sensitivity remains controversial; although it enhanced sensitivity in liposarcoma 143 , it caused resistance in glioblastoma 144 and rhabdomyosarcoma 145 .…”

Section: Targeting Cdks In Cancer Therapymentioning

confidence: 99%

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Cell cycle proteins as promising targets in cancer therapy

2017

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Preface Cancer is characterized by uncontrolled proliferation resulting from aberrant activity of various cell cycle proteins; therefore, cell cycle regulators are considered attractive targets in cancer therapy. Intriguingly, animal models demonstrated that some of these proteins are not essential for proliferation of non-transformed cells and development of most tissues. In contrast, many cancers are uniquely dependent on these proteins and are hence selectively sensitive to their inhibition. After decades of research on the physiological functions of cell cycle proteins and their relevance for cancer, this knowledge recently translated into the first approved cancer therapeutic targeting of a direct regulator of the cell cycle. Here, we review the role of cell cycle proteins in cancer, the rationale for targeting them in cancer treatment and results of clinical trials, as well as future therapeutic potential of various inhibitors. We focus only on proteins that directly regulate cell cycle progression. Cyclin-dependent kinases with transcriptional functions, as well as PARP inhibitors, which are highly successful in targeting BRCA1/BRCA2-mutant tumours, are not covered by this review.

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Section: Targeting Cdks In Cancer Therapymentioning

confidence: 99%

“…Showed synergistic anti-tumour activity with PI3K inhibition in PI3KCA -mutant triple-negative breast cancer xenografts 142 …”

Section: Figurementioning

confidence: 99%

Cell cycle proteins as promising targets in cancer therapy

2017

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“…18,19 Preclinical models found that the basallike 1 and 2 subtypes might be sensitive to platinum salts, the mesenchymal subtype to PI3K pathway inhibition, 16 and the luminal AR subtype to antiandrogen therapy, 16 PI3K inhibitors, 20 and CDK4/6 inhibitors. 21 Although TNBC subtyping has the potential to improve treatment decision ajp.amjpathol.org -The American Journal of Pathology making and an algorithm based on minimal gene sets has been developed, 22 it is unclear whether this classification will have a role in routine clinical practice.…”

Section: Molecular Features Of Conventional Tnbcsmentioning

confidence: 99%

The Spectrum of Triple-Negative Breast Disease

Geyer

Pareja

Weigelt

et al. 2017

The American Journal of Pathology

128

101

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Triple-negative breast cancer is viewed clinically as an aggressive subgroup of breast cancer. In fact, most triple-negative breast cancers are poor-prognosis tumors with a complex genomic landscape. However, triple-negative disease is vastly heterogeneous, encompassing multiple entities with marked genetic, transcriptional, histologic, and clinical differences, with neoplasms in this group ranging from low to high grade. Among the less common low-grade triple-negative lesions, two large subgroups, both with a rather indolent behavior, can be distinguished: a low-grade triple-negative breast neoplasia family, which includes nonobligate precursors of triple-negative breast cancer, and, despite being low-grade, harbors the complex genomic landscape of usual triple-negative breast cancer, and the salivary gland-like tumors of the breast, lacking all the cardinal molecular features of conventional triple-negative breast cancer and underpinned by specific fusion genes or hotspot mutations, which may be of diagnostic and possibly therapeutic utility. Progression to high-grade triple-negative breast cancer likely occurs in both subgroups but at different rates. In this review, we describe the heterogeneity of triple-negative disease, focusing on the histologic and molecular features of the low-grade lesions. Recognition that triple-negative breast cancer is an operational term and that triple-negative disease is heterogeneous and includes low-grade forms driven by distinct sets of genetic alterations is germane to the successful implementation of precision medicine.

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“…81 Although RB protein is commonly lost in TNBC, RB has been associated with AR expression in TNBC, and sensitivity to palbociclib has been reported in three LAR cell lines. 82 , 83 Combination therapy of CDK4/6 inhibitors and androgen deprivation treatment is being evaluated in two ongoing Phase I/II clinical trials ( Table 1 ).…”

Section: Androgen Receptor Targetingmentioning

confidence: 99%

Targeting the androgen receptor in triple-negative breast cancer: current perspectives

Mina

Yoder

Sharma

2017

OTT

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Triple-negative breast cancer (TNBC) is an aggressive subtype associated with frequent recurrence and metastasis. Unlike hormone receptor-positive subtypes, treatment of TNBC is currently limited by the lack of clinically available targeted therapies. Androgen signaling is necessary for normal breast development, and its dysregulation has been implicated in breast tumorigenesis. In recent years, gene expression studies have identified a subset of TNBC that is enriched for androgen receptor (AR) signaling. Interference with androgen signaling in TNBC is promising, and AR-inhibiting drugs have shown antitumorigenic activity in preclinical and proof of concept clinical studies. Recent advances in our understanding of androgenic signaling in TNBC, along with the identification of interacting pathways, are allowing development of the next generation of clinical trials with AR inhibitors. As novel AR-targeting agents are developed and evaluated in clinical trials, it is equally important to establish a robust set of biomarkers for identification of TNBC tumors that are most likely to respond to AR inhibition.

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Identification of subtypes of triple negative breast cancer (TNBC) that are sensitive to CDK4/6 inhibition.

Cited by 16 publications

References 0 publications

Cell cycle proteins as promising targets in cancer therapy

Cell cycle proteins as promising targets in cancer therapy

The Spectrum of Triple-Negative Breast Disease

Targeting the androgen receptor in triple-negative breast cancer: current perspectives

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