Mechanisms of Resistance to CDK4/6 Inhibitors: Potential Implications and Biomarkers for Clinical Practice

McCartney, Amelia; Migliaccio, Ilenia; Bonechi, Martina; Biagioni, Chiara; Romagnoli, Dario; Luca, Francesca De; Galardi, Francesca; Risi, Emanuela; Santo, Irene De; Benelli, Matteo; Malorni, Luca; Leo, Angelo Di

doi:10.3389/fonc.2019.00666

Cited by 130 publications

(131 citation statements)

References 80 publications

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“…Although initially beneficial, resistance to CDK4/6 inhibition arises in almost all patients within two years thus limiting durable responses. Currently, there are no biomarkers that can predict treatment response or early resistance [26]. Here, we identified a number of clinically relevant pathways that are associated with resistance to palbociclib, largely focusing on metabolic alterations and oncogenic signaling such as nucleotide metabolism, inositol metabolism, cell cycle, immune regulation and DDR.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling Identifies Differentially Expressed Genes in Palbociclib-Resistant ER+ MCF7 Breast Cancer Cells

Lanceta

O’Neill

Lypova

et al. 2020

Genes

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Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in estrogen receptor-positive (ER+) breast cancer remains a significant clinical challenge. Efforts to uncover the mechanisms underlying resistance are needed to establish clinically actionable targets effective against resistant tumors. In this study, we sought to identify differentially expressed genes (DEGs) associated with acquired resistance to palbociclib in ER+ breast cancer. We performed next-generation transcriptomic RNA sequencing (RNA-seq) and pathway analysis in ER+ MCF7 palbociclib-sensitive (MCF7/pS) and MCF7 palbociclib-resistant (MCF7/pR) cells. We identified 2183 up-regulated and 1548 down-regulated transcripts in MCF7/pR compared to MCF7/pS cells. Functional analysis of the DEGs using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database identified several pathways associated with breast cancer, including ‘cell cycle’, ‘DNA replication’, ‘DNA repair’ and ‘autophagy’. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with deregulation of several key canonical and metabolic pathways. Further studies are needed to determine the utility of these DEGs and pathways as therapeutics targets against ER+ palbociclib-resistant breast cancer.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling Identifies Differentially Expressed Genes in Palbociclib-Resistant ER+ MCF7 Breast Cancer Cells

Lanceta

O’Neill

Lypova

et al. 2020

Genes

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“…CDK4/6 inhibitors were approved by the FDA for the treatment of Hormone Receptor (HR)-positive and Human Epidermal Growth Factor Receptor 2 (HER2)-negative breast cancer. However, most patients inevitably develop resistance for multifactorial reasons [30,31]. Recently, our group demonstrated that the JAK-STAT pathway plays a role in acquired resistance of CDK4/6 inhibitors in bladder cancer [32].…”

Section: Introductionmentioning

confidence: 99%

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

Hindupur

Schmid

Koch

et al. 2020

IJMS

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The JAK-STAT signalling pathway regulates cellular processes like cell division, cell death and immune regulation. Dysregulation has been identified in solid tumours and STAT3 activation is a marker for poor outcome. The aim of this study was to explore potential therapeutic strategies by targeting this pathway in bladder cancer (BC). High STAT3 expression was detected in 51.3% from 149 patient specimens with invasive bladder cancer by immunohistochemistry. Protein expression of JAK, STAT and downstream targets were confirmed in 10 cell lines. Effects of the JAK inhibitors Ruxolitinib and BSK-805, and STAT3/5 inhibitors Stattic, Nifuroxazide and SH-4-54 were analysed by cell viability assays, immunoblotting, apoptosis and cell cycle progression. Treatment with STAT3/5 but not JAK1/2 inhibitors reduced survival, levels of phosphorylated STAT3 and Cyclin-D1 and increased apoptosis. Tumour xenografts, using the chicken chorioallantoic membrane (CAM) model responded to Stattic monotherapy. Combination of Stattic with Cisplatin, Docetaxel, Gemcitabine, Paclitaxel and CDK4/6 inhibitors showed additive effects. The combination of Stattic with the oncolytic adenovirus XVir-N-31 increased viral replication and cell lysis. Our results provide evidence that inhibitors against STAT3/5 are promising as novel mono- and combination therapy in bladder cancer.

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“…This approach has been used previously and generated clinically relevant results, identifying cyclin E1 overexpression and Rb loss as genetic traits of palbociclib resistance [13,29,30]. Importantly, mammalian target of rapamycin complex 1 (mTORC1) activation is also reported to play an important role in the resistance mechanism and, currently, PI3K inhibitors (i.e., blocking PI3K/mTOR pathway) are in clinical trials in combination with CDK4/6 inhibitors [31]. Importantly, mTOR activation has also been reported to enhance glycolytic traits of the resistant cells, suggesting that glycolytic function may be under PI3K/mTOR signaling control in cancer and other pathologies [17].…”

Section: Discussionmentioning

confidence: 99%

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

Lorito

Bacci

Smiriglia

et al. 2020

Cells

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The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER+)/human epidermal growth factor receptor 2 negative (HER2−) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER+/HER2+ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER+ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER+/HER2− and ER+/HER2+ cell lines show a different degree of glucose dependency. While ER+/HER2− breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER+/HER2+ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance.

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Mechanisms of Resistance to CDK4/6 Inhibitors: Potential Implications and Biomarkers for Clinical Practice

Cited by 130 publications

References 80 publications

Transcriptomic Profiling Identifies Differentially Expressed Genes in Palbociclib-Resistant ER+ MCF7 Breast Cancer Cells

Transcriptomic Profiling Identifies Differentially Expressed Genes in Palbociclib-Resistant ER+ MCF7 Breast Cancer Cells

STAT3/5 Inhibitors Suppress Proliferation in Bladder Cancer and Enhance Oncolytic Adenovirus Therapy

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib+

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