scholarly journals High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer

2021 ◽  
Author(s):  
Marta Palafox ◽  
Laia Monserrat ◽  
Meritxell Bellet ◽  
Guillermo Villacampa ◽  
Abel Gonzalez-Perez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
De Novo ◽  
Acquired Resistance ◽  
Poor Clinical Outcome ◽  
Cyclin Dependent Kinases ◽  
Estrogen Receptor Positive ◽  
Inhibitor Resistance ◽  
P16 Expression ◽  
P16 Overexpression

Abstract Cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), combined with endocrine therapy (ET), have demonstrated higher antitumor activity than ET alone for the treatment of advanced estrogen receptor-positive (ER+) breast cancer (BC). Some ER+ BC are de novo resistant to CDK4/6i and others develop acquired resistance. Therapies for tumors after progression are needed. Here, we demonstrate that p16 overexpression is associated with reduced antitumor activity of CDK4/6i in patient-derived xenografts (PDX; n=37) and ER+ BC cell lines, and reduced response of early/advanced ER+HER2- BC patients (n=49) to CDK4/6i. We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome in ER+, CDK4/6i-treated BC PDX and patients. Combination of CDK4/6i ribociclib with PI3K inhibitor (PI3Ki) alpelisib showed antitumor activity in ER+ non-basal-like BC PDX, independently of PIK3CA or RB1 mutation (n=25). Our results offer new insights into predicting primary and acquired resistance to CDK4/6i and post-progression therapeutic strategies.

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

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 467 ◽  
Author(s):  
Lilibeth Lanceta ◽  
Conor O'Neill ◽  
Nadiia Lypova ◽  
Xiahong Li ◽  
Eric Rouchka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Differentially Expressed Genes ◽  
Pathway Analysis ◽  
Metabolic Pathways ◽  
Acquired Resistance ◽  
Differentially Expressed ◽  
Rna Seq ◽  
Kegg Database ◽  
Cyclin Dependent Kinases ◽  
Estrogen Receptor Positive

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.

scholarly journals Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

2021 ◽  
Vol 22 (22) ◽  
pp. 12292
Author(s):  
Erin R. Scheidemann ◽  
Ayesha N. Shajahan-Haq
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Cycle Progression ◽  
Acquired Resistance ◽  
Alternative Methods ◽  
Cycle Progression ◽  
Estrogen Receptor Positive ◽  
New Treatment ◽  
Methods Of Treatment

Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.

scholarly journals HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species

2019 ◽  
Vol 12 (601) ◽  
pp. eaay0482 ◽  
Author(s):  
Hilary E. Nicholson ◽  
Zeshan Tariq ◽  
Benjamin E. Housden ◽  
Rebecca B. Jennings ◽  
Laura A. Stransky ◽  
...  
Keyword(s):  
Clear Cell ◽  
De Novo ◽  
Synthetic Lethality ◽  
Acquired Resistance ◽  
Hypoxia Inducible Factor ◽  
Suppressor Gene ◽  
Cell Renal Cell Carcinoma ◽  
Antiproliferative Effects ◽  
Cyclin Dependent Kinases ◽  
Ccrcc Cell

Inactivation of the VHL tumor suppressor gene is the signature initiating event in clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, and causes the accumulation of hypoxia-inducible factor 2α (HIF-2α). HIF-2α inhibitors are effective in some ccRCC cases, but both de novo and acquired resistance have been observed in the laboratory and in the clinic. Here, we identified synthetic lethality between decreased activity of cyclin-dependent kinases 4 and 6 (CDK4/6) and VHL inactivation in two species (human and Drosophila) and across diverse human ccRCC cell lines in culture and xenografts. Although HIF-2α transcriptionally induced the CDK4/6 partner cyclin D1, HIF-2α was not required for the increased CDK4/6 requirement of VHL−/− ccRCC cells. Accordingly, the antiproliferative effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α–dependent VHL−/− ccRCC cells and not antagonistic with HIF-2α inhibition in HIF-2α–independent cells. These findings support testing CDK4/6 inhibitors as treatments for ccRCC, alone and in combination with HIF-2α inhibitors.

scholarly journals Mechanisms of CDK4/6 Inhibitor Resistance in Luminal Breast Cancer

2020 ◽  
Vol 11 ◽  
Author(s):  
Zhen Li ◽  
Wei Zou ◽  
Ji Zhang ◽  
Yunjiao Zhang ◽  
Qi Xu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Luminal Breast Cancer ◽  
Cancer Drug Resistance ◽  
Estrogen Receptor Positive ◽  
Underlying Mechanisms ◽  
Inhibitor Resistance ◽  
New Generation

As a new-generation CDK inhibitor, a CDK4/6 inhibitor combined with endocrine therapy has been successful in the treatment of advanced estrogen receptor–positive (ER+) breast cancer. Although there has been overall progress in the treatment of cancer, drug resistance is an emerging cause for breast cancer–related death. Overcoming CDK4/6 resistance is an urgent problem. Overactivation of the cyclin-CDK-Rb axis related to uncontrolled cell proliferation is the main cause of CDK4/6 inhibitor resistance; however, the underlying mechanisms need to be clarified further. We review various resistance mechanisms of CDK4/6 inhibitors in luminal breast cancer. The cell signaling pathways involved in therapy resistance are divided into two groups: upstream response mechanisms and downstream bypass mechanisms. Finally, we discuss possible strategies to overcome CDK4/6 inhibitor resistance and identify novel resistance targets for future clinical application.

scholarly journals Modeling Breast Cancer Using CRISPR-Cas9–Mediated Engineering of Human Breast Organoids

2019 ◽  
Vol 112 (5) ◽  
pp. 540-544 ◽  
Author(s):  
Johanna F Dekkers ◽  
James R Whittle ◽  
François Vaillant ◽  
Huei-Rong Chen ◽  
Caleb Dawson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor Genes ◽  
De Novo ◽  
Clonal Evolution ◽  
Genetic Alterations ◽  
Patient Treatment ◽  
Normal Epithelium ◽  
Molecular Events ◽  
Estrogen Receptor Positive

Abstract Breast cancer is characterized by histological and functional heterogeneity, posing a clinical challenge for patient treatment. Emerging evidence suggests that the distinct subtypes reflect the repertoire of genetic alterations and the target cell. However, the precise initiating events that predispose normal epithelium to neoplasia are poorly understood. Here, we demonstrate that breast epithelial organoids can be generated from human reduction mammoplasties (12 out of 12 donors), thus creating a tool to study the clonal evolution of breast cancer. To recapitulate de novo oncogenesis, we exploited clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 for targeted knockout of four breast cancer–associated tumor suppressor genes (P53, PTEN, RB1, NF1) in mammary progenitor cells from six donors. Mutant organoids gained long-term culturing capacity and formed estrogen-receptor positive luminal tumors on transplantation into mice for one out of six P53/PTEN/RB1–mutated and three out of six P53/PTEN/RB1/NF1–mutated lines. These organoids responded to endocrine therapy or chemotherapy, supporting the potential utility of this model to enhance our understanding of the molecular events that culminate in specific subtypes of breast cancer.

scholarly journals Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response

Breast Care ◽  
2017 ◽  
Vol 12 (5) ◽  
pp. 304-308 ◽  
Author(s):  
Cristina Guarducci ◽  
Martina Bonechi ◽  
Giulia Boccalini ◽  
Matteo Benelli ◽  
Emanuela Risi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Molecular Mechanisms ◽  
Randomized Clinical Trials ◽  
De Novo ◽  
Current Knowledge ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Molecular Alterations ◽  
Potential Biomarkers

Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting. In addition, molecular mechanisms of acquired resistance to palbociclib have been analyzed only in preclinical studies. Here we review the current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response.

scholarly journals Generation and characterisation of an estrogen receptor-positive GEMM-derived Pten p53 null transplantable breast tumour model for therapeutic testing

2019 ◽  
Author(s):  
E.J. Davies ◽  
H. Morgan ◽  
G. Tornillo ◽  
C.D. Chabbert ◽  
H. Kendrick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
De Novo ◽  
Breast Tumour ◽  
Genetically Engineered ◽  
Early Passage ◽  
Pharmacological Agents ◽  
Long Latency ◽  
Tumour Implantation ◽  
Estrogen Receptor Positive ◽  
Transplantable Tumour

AbstractAssessing the signalling pathway dependencies of tumours that arise autochthonously in genetically engineered mouse models (GEMMs) of breast cancer is particularly challenging due to the high degree of intra- and inter-tumour heterogeneity, as well as the long latency of tumour development in such models. Use of transplantable tumour lines derived from autochthonous tumours (‘Mouse Derived Xenografts’ or MDXs) is one possible solution and has been used successfully in models of BRCA1-associated triple negative breast cancer. However, their potential in ER+ breast cancer models has not been addressed. Here, we assess the utility of orthotopic transplantable tumour lines derived from an autochthonous ER+ Blg-cre Ptenfl/fl p53fl/fl breast cancer model. We show that initial tumour implantation and early passage results in the development of lines of progeny with heterogeneous histopathological phenotypes which is coincident with an accumulation of, or selection for, de novo mutations. Importantly, these lines also display different dependencies on the key pathways that drive tumourigenesis, which can lead to inherent resistance to treatment with pharmacological agents targeting these pathways and makes them important models to test strategies to overcome such resistance.

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