Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

Li, Zhen; Zou, Wei; Zhang, Ji; Zhang, Yunjiao; Xu, Qi; Liu, Siyuan; Chen, Ceshi

doi:10.3389/fphar.2020.580251

Cited by 54 publications

(40 citation statements)

References 113 publications

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“…Some studies have considered the efficacy of Olaparib in ATM -deficient leukemic cells from patients with leukemia [ 68 ] or in patients with gastric cancer [ 69 ], but no studies in BC tumor cells have yet been performed. The ATM -dependent pathway is also involved in resistance to treatment with CDK4/6 inhibitors, recently introduced in clinical practice for the treatment of advanced estrogen receptor-positive BC [ 70 ]. In this regard, a recent study showed that defects in single-strand break repair in luminal BC can drive endocrine therapy resistance and are closely associated with the ATM-CHK2-CDC25A pathway.…”

Section: Therapeutic Implications Of Atm Gene Mutations In Bcmentioning

confidence: 99%

The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice

Stucci

Internò

Tucci

et al. 2021

Genes

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Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated (ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.

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Section: Therapeutic Implications Of Atm Gene Mutations In Bcmentioning

confidence: 99%

The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice

Stucci

Internò

Tucci

et al. 2021

Genes

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“…Endocrine therapies remain the best option for ER+ patients (luminal cancers), but the development of drug resistance is problematic. Patients can also develop resistance to CDK4 inhibitors (25), three of which are approved for clinical use (26). Identifying new targetable oncogenes will advance knowledge on the evolution and progression of cancer and reveal novel treatment approaches that improve the prognosis and long-term survival of cancer patients, especially those that develop resistance to front-line therapies.…”

Section: Introductionmentioning

confidence: 99%

Chaperonin-Containing TCP1 Complex (CCT) Promotes Breast Cancer Growth Through Correlations With Key Cell Cycle Regulators

et al. 2021

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Uncontrolled proliferation as a result of dysregulated cell cycling is one of the hallmarks of cancer. Therapeutically targeting pathways that control the cell cycle would improve patient outcomes. However, the development of drug resistance and a limited number of inhibitors that target multiple cell cycle modulators are challenges that impede stopping the deregulated growth that leads to malignancy. To advance the discovery of new druggable targets for cell cycle inhibition, we investigated the role of Chaperonin-Containing TCP1 (CCT or TRiC) in breast cancer cells. CCT, a type II chaperonin, is a multi-subunit protein-folding complex that interacts with many oncoproteins and mutant tumor suppressors. CCT subunits are highly expressed in a number of cancers, including breast cancer. We found that expression of one of the CCT subunits, CCT2, inversely correlates with breast cancer patient survival and is subject to copy number alterations through genomic amplification. To investigate a role for CCT2 in the regulation of the cell cycle, we expressed an exogenous CCT2-FLAG construct in T47D and MCF7 luminal A breast cancer cells and examined cell proliferation under conditions of two-dimensional (2D) monolayer and three-dimensional (3D) spheroid cultures. Exogenous CCT2 increased the proliferation of cancer cells, resulting in larger and multiple spheroids as compared to control cells. CCT2-expressing cells were also able to undergo spheroid growth reversal, re-attaching, and resuming growth in 2D cultures. Such cells gained anchorage-independent growth. CCT2 expression in cells correlated with increased expression of MYC, especially in spheroid cultures, and other cell cycle regulators like CCND1 and CDK2, indicative of a novel activity that could contribute to the increase in cell growth. Statistically significant correlations between CCT2, MYC, and CCND1 were shown. Since CCT2 is located on chromosome 12q15, an amplicon frequently found in soft tissue cancers as well as breast cancer, CCT2 may have the basic characteristics of an oncogene. Our findings suggest that CCT2 could be an essential driver of cell division that may be a node through which pathways involving MYC, cyclin D1 and other proliferative factors could converge. Hence the therapeutic inhibition of CCT2 may have the potential to achieve multi-target inhibition, overcoming the limitations associated with single agent inhibitors.

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“…All these drugs are already clinically available. In addition, data from other cancer types suggest several more putative mechanisms of resistance [60]: CDK4/6 overexpression [61], p16 amplification [62,63], upregulation of FGFR pathway [64,65], alteration of Hippo pathway [66], activation of CDK2 [67,68], autophagy [69], and epigenetic alterations [70,71].…”

Section: Resistance Mechanisms To Cdk4/6 Inhibitorsmentioning

confidence: 99%

CDK4/6 Inhibitors in Melanoma: A Comprehensive Review

Garutti

Targato

Buriolla

et al. 2021

Cells

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Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials.

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Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

Cited by 54 publications

References 113 publications

The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice

The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice

Chaperonin-Containing TCP1 Complex (CCT) Promotes Breast Cancer Growth Through Correlations With Key Cell Cycle Regulators

CDK4/6 Inhibitors in Melanoma: A Comprehensive Review

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