Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells

Ogata, Ryohei; Kishino, Emi; Saitoh, Wataru; Koike, Yoshikazu; Kurebayashi, Junichi

doi:10.1007/s12282-020-01150-8

Cited by 24 publications

(18 citation statements)

References 15 publications

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“…Another limitation of the current analysis is the use of cells that are resistant to a single CDK4/6 inhibitor, palbociclib. Preclinical evidence in some ER+ models suggests that resistance to palbociclib confers cross-resistance to the other CDK4/6 inhibitors and thus, it is likely that a number of mechanisms of resistance described here will be shared with other CDK4/6 inhibitors [45]. Nevertheless, the data presented here will help guide future efforts to study these potentially targetable alterations in response to CDK4/6 inhibition in TNBC.…”

Section: Discussionmentioning

confidence: 74%

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Lanceta

Lypova

O’Neill

et al. 2021

Breast Cancer Res Treat

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Purpose The management of triple-negative breast cancer (TNBC) remains a significant clinical challenge due to the lack of effective targeted therapies. Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) are emerging as promising therapeutic agents against TNBC; however, cells can rapidly acquire resistance through multiple mechanisms that are yet to be identified. Therefore, determining the mechanisms underlying resistance to CDK4/6 inhibition is crucial to develop combination therapies that can extend the efficacy of the CDK4/6 inhibitors or delay resistance. This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER− breast cancer cells. Methods We performed next-generation transcriptomic sequencing (RNA-seq) and pathway analysis in ER− MDA-MB-231 palbociclib-sensitive (231/pS) and palbociclib-resistant (231/pR) cells. Results We identified 2247 up-regulated and 1427 down-regulated transcripts in 231/pR compared to 231/pS cells. DEGs were subjected to functional analysis using Gene Ontology (GO) and the KEGG database which identified many transduction pathways associated with breast cancer, including the PI3K/AKT, PTEN and mTOR pathways. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with altered cholesterol and fatty acid biosynthesis suggesting that resistance to palbociclib may be dependent on lipid metabolic reprograming. Conclusion This study provides evidence that lipid metabolism is altered in TNBC with acquired resistance to palbociclib. Further studies are needed to determine if the observed lipid metabolic rewiring can be exploited to overcome therapy resistance in TNBC.

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Section: Discussionmentioning

confidence: 74%

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Lanceta

Lypova

O’Neill

et al. 2021

Breast Cancer Res Treat

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“…Preclinical data are discordant, as some studies show that CDK4/6i doesn’t have cross-resistance in cellular models, while other studies highlight some mechanism of resistance shared between different CDK4/6i [ 64 ].…”

Section: Treatment Strategies After Cdk4/6i: What Is Known What Is On...mentioning

confidence: 99%

How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story

Cogliati¹,

Capici²,

Pepe³

et al. 2022

Life

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CDK4/6 inhibitors in association with endocrine therapy represent the best therapeutic choice for either endocrine-sensitive or resistant hormone-receptor-positive advanced breast cancer patients. On the contrary, the optimal therapeutic strategy after the failure of CDK4/6 inhibitors-based treatment still remains an open question worldwide. In this review, we analyze the most studied mechanisms of resistance to CDK4/6 inhibitors treatment, as well as the most significant results of retrospective and prospective trials in the setting of progression after CDK4/6 inhibitors, to provide the reader a comprehensive overview from both a preclinical and especially a clinical perspective. In our opinion, an approach based on a deeper knowledge of resistance mechanisms to CDK4/6 inhibitors, but also on a careful analysis of what is done in clinical practice, can lead to a better definition of prospective randomized trials, to implement a personalized sequence approach, based on molecular analyses.

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“…Whether CDK4/6i treatment should be continued beyond the development of disease progression remains to be defined. Recent preclinical studies reported cross-resistance between the three approved CDK4/6i in palbociclib-resistant breast cancer cell models [60,61]. However, some studies suggest that a substantial number of patients continue to derive clinical benefit with abemaciclib after prior palbociclib or ribociclib treatment [62][63][64].…”

Section: Role Of Cdk4/6i After Disease Progressionmentioning

confidence: 99%

Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

Al-Qasem

Alves

Ditzel

2021

Cancers

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The introduction of CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) has revolutionized the treatment landscape for patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) and has become the new standard treatment. However, resistance to this combined therapy inevitably develops and represents a major clinical challenge in the management of ER+ ABC. Currently, elucidation of the resistance mechanisms, identification of predictive biomarkers, and development of novel effective combined targeted treatments to overcome the resistance are active areas of research. Given the heterogeneity of the resistance mechanisms towards combined CDK4/6i and ET, identification of a single universal predictive biomarker of resistance is unlikely. Novel approaches are being explored, including examination of multiple genetic alterations in circulating cell-free tumor DNA in liquid biopsies from ABC patients with disease progression on combined CDK4/6i and ET treatment. Here, we review the molecular basis of the main known resistance mechanisms towards combined CDK4/6i and ET and associated potential biomarkers. As inhibiting key molecules in the pathways driving resistance may play an important role in the selection of therapeutic strategies for patients who experience disease progression on combined CDK4/6i and ET, we also review preclinical and early phase clinical data on novel combination therapies for these patients.

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Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors confers cross-resistance to other CDK inhibitors but not to chemotherapeutic agents in breast cancer cells

Cited by 24 publications

References 15 publications

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

How to Treat HR+/HER2- Metastatic Breast Cancer Patients after CDK4/6 Inhibitors: An Unfinished Story

Resistance Mechanisms to Combined CDK4/6 Inhibitors and Endocrine Therapy in ER+/HER2− Advanced Breast Cancer: Biomarkers and Potential Novel Treatment Strategies

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