PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence

Klein, Mary E.; Dickson, Mark A.; Antonescu, Cristina R.; Qin, Li‐Xuan; Dooley, Scott J.; Barlas, Afsar; Manova, Katia; Schwartz, Gary K.; Crago, Aimeé M.; Singer, Samuel; Koff, Andrew; Tap, William D.

doi:10.1038/s41388-018-0332-y

Cited by 42 publications

(27 citation statements)

References 38 publications

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“…Thus, in our models of resistance to either endocrine therapy or palbociclib, NVP-CGM097-mediated induction of G 2 /M accumulation along with the downregulation of FOXM1 and other senescence-related transcripts appears to be sufficient to trigger entry into senescence. CDK4/6 inhibitors are known to increase senescence entry and MDM2 can counteract this [44].…”

Section: Discussionmentioning

confidence: 99%

MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer

et al. 2020

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Background: Resistance to endocrine therapy is a major clinical challenge in the management of oestrogen receptor (ER)-positive breast cancer. In this setting, p53 is frequently wildtype and its activity may be suppressed via upregulation of its key regulator MDM2. This underlies our rationale to evaluate MDM2 inhibition as a therapeutic strategy in treatment-resistant ER-positive breast cancer. Methods: We used the MDM2 inhibitor NVP-CGM097 to treat in vitro and in vivo models alone and in combination with fulvestrant or palbociclib. We perform cell viability, cell cycle, apoptosis and senescence assays to evaluate antitumour effects in p53 wildtype and p53 mutant ER-positive cell lines (MCF-7, ZR75-1, T-47D) and MCF-7 lines resistant to endocrine therapy and to CDK4/6 inhibition. We further assess the drug effects in patient-derived xenograft (PDX) models of endocrine-sensitive and endocrine-resistant ER-positive breast cancer. Results: We demonstrate that MDM2 inhibition results in cell cycle arrest and increased apoptosis in p53-wildtype in vitro and in vivo breast cancer models, leading to potent anti-tumour activity. We find that endocrine therapy or CDK4/ 6 inhibition synergises with MDM2 inhibition but does not further enhance apoptosis. Instead, combination treatments result in profound regulation of cell cycle-related transcriptional programmes, with synergy achieved through increased antagonism of cell cycle progression. Combination therapy pushes cell lines resistant to fulvestrant or palbociclib to become senescent and significantly reduces tumour growth in a fulvestrant-resistant patient-derived xenograft model. Conclusions: We conclude that MDM2 inhibitors in combination with ER degraders or CDK4/6 inhibitors represent a rational strategy for treating advanced, endocrine-resistant ER-positive breast cancer, operating through synergistic activation of cell cycle co-regulatory programmes.

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Section: Discussionmentioning

confidence: 99%

MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer

et al. 2020

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“…Cellular senescence is a state of irreversible cell cycle arrest that can be triggered by various cell-intrinsic and extrinsic stimuli, including DNA damage, oxidative stress, and exposure to chemotherapeutic agents and ionizing radiation [10]. Although the induction of apoptotic cell death was thought to be a desirable outcome for cancer therapy, we and others have shown that senescence induction in tumor cells is a common therapeutic response to many anticancer modalities including CDK4/6 small molecule inhibitor-based targeted therapeutics and radiation treatment [10][11][12][13][14][15]. In this study, we demonstrate that H 2 O 2mediated oxidative stress induces premature senescence, but not apoptosis in BCSCs.…”

Section: Introductionmentioning

confidence: 99%

Oxidative stress induces senescence in breast cancer stem cells

Zhong

Qin

Townsend

et al. 2019

Biochemical and Biophysical Research Communications

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Cancer stem cells (CSCs) have been shown to be resistant to current anticancer therapies and the induction of oxidative stress is an important mechanism of action for many anticancer agents. However, it is still largely unknown how CSCs respond to hydrogen peroxide (H 2 O 2)-induced oxidative stress. Here, we show that the levels of reactive oxygen species (ROS) are markedly lower in breast CSCs (BCSCs) than that in non-cancer stem cells (NCSCs). A transient exposure of breast cancer cells to sublethal doses of H 2 O 2 resulted in a dose-dependent increase of the epithelium-specific antigen (ESA) + /CD44 + /CD24 − subpopulations, a known phenotype for BCSCs. Although BCSCs survived sublethal doses of H 2 O 2 treatment, they lost the ability to form tumor spheres and failed to generate colonies as demonstrated by mammosphere-formation and clonogenic assays, respectively. Mechanistic studies revealed that H 2 O 2 treatment led to a marked increase of senescence-associated β-galactosidase activity but only minimal apoptotic cell death in BCSCs. Furthermore, H 2 O 2 triggers p53 activation and promotes p21 expression, indicating a role for the p53/p21 signaling pathway in oxidative stress-induced senescence in BCSCs. Taken together, these results demonstrate that the maintenance of a lower level of ROS is critical for CSCs to avoid oxidative stress and H 2 O 2-induced BCSC loss of function is likely attributable to oxidative stress-triggered senescence induction, suggesting that ROS-generating drugs may have the therapeutic potential to eradicate drug-resistant CSCs via induction of premature senescence.

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“…Association with the STS type-dominated transcriptome clusters was negatively correlated with subclonality of the 64 SCNAs ( Figure 3D), consistent with the assumption of these being intrinsic STS type-specific events. Regions of strongest subtype association and concomitantly low subclonality included the MDM2 amplification ( Figure 4 top right), previously reported to be a key driver of DDLPS and MFS/UPS, but rarely occurring in LMS [19,21]. A notable exception from the observed trend was the TP73 -containing telomeric deletion on chromosome 1 that occurred predominantly subclonal in sarcomas assigned to the DDLPS and MFS/UPS clusters, yet predominantly clonal in the LMS cluster (Figure 4 bottom right).…”

Section: Correlation Of Subtype Association With Subclonalitymentioning

confidence: 99%

Multi-omic analysis of subtype evolution and heterogeneity in high-grade serous ovarian carcinoma

Ramos

Schiffer

et al. 2019

Preprint

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Background: The majority of ovarian carcinomas are of high-grade serous histology, which is associated with poor prognosis and limited treatment options. Several studies have identified gene expression-based subtypes of high-grade serous ovarian carcinoma (HGSOC) as a basis for targeted therapy, yet extensive ambiguity in subtype classification impairs translation of these subtypes into clinical practice. Furthermore, although HGSOC tumors are known to be frequently polyclonal, it is unknown whether clones within the same tumor share the same subtype. Results:We investigate whether ambiguity in subtype classification can be attributed to the polyclonal composition of HGSOC tumors, addressing the currently unresolved question whether proposed subtypes are early or late events in tumorigenesis. This hypothesis is first tested in The Cancer Genome Atlas HGSOC cases by (i) analyzing recurrent somatic copy number alterations for their association with subtypes, (ii) inferring per-alteration clonality from complementary analysis of SNP arrays and whole-exome sequencing, and (iii) testing whether subtype-associated alterations tend to predominantly occur clonally (early events) or subclonally (late events). As opposed to the genomically distinct evolution of soft-tissue sarcoma subtypes, we find that subtype association of HGSOC alterations significantly correlate with subclonality. This correlation is particularly evident for the high-purity proliferative subtype spectrum, which is also characterized by extreme genomic instability, absence of immune infiltration, and increased patient age. This is in stark contrast to the high-purity differentiated subtype spectrum, which is characterized by largely intact genome integrity, high immune infiltration, and younger patient age. Other subtypes showed intermediate levels for these characteristics. From single cell sequencing of an independent HGSOC tumor, we demonstrate that ambiguity in subtype classification extends to individual tumor epithelial cells, further supporting a developmental transition from one subtype spectrum to another. Conclusion:We propose a novel model of HGSOC tumor development that complements the subtype perspective. In this model, individual tumors develop from an early differentiated spectrum to a late proliferative spectrum, and may exhibit characteristics of different previously defined "subtypes" at different points along a timeline characterized by increasing genomic instability and subclonal expansion. This model is more consistent with available bulk and single-cell data, and provides an explanation for ambiguity in subtype classification as the result of assigning discrete, mutually exclusive subtypes to a genomically complex process of tumor evolution.

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PDLIM7 and CDH18 regulate the turnover of MDM2 during CDK4/6 inhibitor therapy-induced senescence

Cited by 42 publications

References 38 publications

MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer

MDM2 inhibition in combination with endocrine therapy and CDK4/6 inhibition for the treatment of ER-positive breast cancer

Oxidative stress induces senescence in breast cancer stem cells

Multi-omic analysis of subtype evolution and heterogeneity in high-grade serous ovarian carcinoma

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