CDK4/6 inhibitors promote senescence-associated lysosomal alterations and enhance sensitivity to lysosomotropic agents in breast cancer DOI Creative Commons
Jamil Nehme, Sjors Maassen, Sara Bravaccini

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 23, 2024

Abstract Breast cancer is a leading cause of mortality worldwide. Pharmacological inhibitors Cyclin- Dependent Kinases (CDK) 4 and 6 (CDK4/6i) inhibit breast growth by inducing senescent-like state. However, the long-term treatment efficacy remains hindered development drug resistance. Clearance cells may extend durability treatment. In this study, we showed that CDK4/6i-treated exhibit various senescence-associated phenotypes, but remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, identified significantly increased lysosomal mass altered structure across cell types upon exposure CDK4/6i in preclinical systems clinical specimens. We demonstrated these alterations render sensitive lysosomotropic agents, such as L- leucyl-L-leucine methyl ester (LLOMe) salinomycin. Importantly, sequential with CDK4/6i/lysosomotropic agents effectively reduced both Hormone Receptor- positive (HR + ) triple-negative (TNBC) vivo. This therapeutic strategy offers promising approach eliminate CDK4/6i-induced senescent(-like) cells, potentially reducing tumor recurrence enhancing overall therapy.

Language: Английский

Pharmacological CDK4/6 inhibition promotes vulnerability to lysosomotropic agents in breast cancer DOI Creative Commons
Jamil Nehme, Sjors Maassen, Sara Bravaccini

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 10, 2025

Breast cancer is a leading cause of mortality worldwide. Pharmacological inhibitors cyclin-dependent kinases (CDK) 4 and 6 (CDK4/6i) inhibit breast growth by inducing senescent-like state. However, the long-term treatment efficacy remains limited development drug resistance, so clearance cells may extend durability treatment. we show here that while CDK4/6i-treated exhibit various senescence-associated phenotypes, they remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, identify significantly increased lysosomal mass altered structure across cell types upon exposure CDK4/6i in preclinical systems clinical specimens. We demonstrate these CDK4/6i-induced alterations render sensitive lysosomotropic agents, such as L-leucyl-L-leucine methyl ester (LLOMe) salinomycin. Importantly, sequential with agents effectively reduces both hormone receptor-positive (HR+) subsets triple-negative (TNBC) vivo. This therapeutic strategy offers promising approach eliminate senescent(-like) cells, potentially reducing tumor recurrence enhancing overall therapy.

Language: Английский

Citations

1
The Cytoprotective and Cytotoxic Functions of Autophagy in Response to mTOR Inhibitors DOI Creative Commons
Ahmed M. Elshazly,

Aya A. Elzahed,

David A. Gewirtz

et al.

Frontiers in Bioscience-Landmark, Journal Year: 2024, Volume and Issue: 29(6), P. 231 - 231

Published: June 24, 2024

The inhibitors of mammalian target rapapmycin (mTOR), everolimus, temsirolimus and rapamycin, have a wide range clinical utility; however, as is inevitably the case with other chemotherapeutic agents, resistance development constrains their effectiveness. One putative mechanism promotion autophagy, which direct consequence inhibition mTOR signaling pathway. Autophagy primarily considered to be cytoprotective survival mechanism, whereby cytoplasmic components are recycled generate energy metabolic intermediates. autophagy induced by everolimus appears play largely protective function, whereas cytotoxic function predominate in rapamycin. In this review we provide an overview response different tumor models effort determine whether targeting could utility adjuvant therapy association inhibition.

Language: Английский

Citations

4
Pharmacological Modulation of Cellular Senescence: Implications for Breast Cancer Progression and Therapeutic Strategies DOI

Jialing Xie,

Xinxin Shu,

Zilan-Xie

et al.

European Journal of Pharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 177475 - 177475

Published: March 1, 2025

Language: Английский

Citations

0
Steroid signaling in autophagy DOI Creative Commons
I Bradić, Kim Rewitz

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169134 - 169134

Published: April 1, 2025

Autophagy is a conserved cellular process essential for homeostasis and development that plays central role in the degradation recycling of components. Recent studies reveal bidirectional interactions between autophagy steroid-hormone signaling. Steroids are signaling molecules synthesized from cholesterol regulate key physiological developmental processes - including autophagic activity. Conversely, other work demonstrates regulates steroid production by controlling availability precursor sterol substrate. Insights Drosophila mammalian models provide compelling evidence conservation these mechanisms across species. In this review we explore how hormones modulate diverse tissues contexts, such as metabolism disease, discuss advances our understanding autophagy's regulatory hormone production. We examine implications health disease offer perspectives on potential harnessing functionality addressing cholesterol-related disorders.

Language: Английский

Citations

0
Autophagy is required for mammary tumor recurrence by promoting dormant tumor cell survival following therapy DOI Creative Commons

Samantha L. Dwyer,

Jason R. Ruth,

Hans E. Seidel

et al.

Breast Cancer Research, Journal Year: 2024, Volume and Issue: 26(1)

Published: Oct. 18, 2024

Mortality from breast cancer is principally due to tumor recurrence. Recurrent cancers arise the pool of residual cells, termed minimal disease, that survive treatment and may exist in a dormant state for 20 years or more following primary tumor. As recurrent typically incurable, understanding mechanisms underlying cell survival critical priority research. The importance this goal further underscored by emerging evidence suggesting targeting cells early-stage patients be means prevent recurrence its associated mortality. In regard, role autophagy remains unresolved, with conflicting reports both pro-survival/recurrence-promoting pro-death/recurrence-suppressing effects inhibition cells. Resolving question has important clinical implications. We used genetically engineered mouse models faithfully recapitulate key features human progression, including dormancy, genetic pharmacological approaches inhibit autophagy, chloroquine, knockdown ATG5 ATG7, deletion BECN determined their on demonstrate mammary therapy dependent upon autophagy. find induced vivo HER2 downregulation activated Using we show inhibiting chloroquine administration, ATG7 knockdown, single allele suppressor Beclin 1 sufficient recurrence, results death vivo. Our findings pro-tumorigenic dormancy therapy, reveal are uniquely reliant survival, indicate impairs These studies identify target cellular resistant commonly anti-neoplastic agents suggest as an approach reduce disease order lethal

Language: Английский

Citations

1
CDK4/6 inhibitors promote senescence-associated lysosomal alterations and enhance sensitivity to lysosomotropic agents in breast cancer DOI Creative Commons
Jamil Nehme, Sjors Maassen, Sara Bravaccini

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 23, 2024

Abstract Breast cancer is a leading cause of mortality worldwide. Pharmacological inhibitors Cyclin- Dependent Kinases (CDK) 4 and 6 (CDK4/6i) inhibit breast growth by inducing senescent-like state. However, the long-term treatment efficacy remains hindered development drug resistance. Clearance cells may extend durability treatment. In this study, we showed that CDK4/6i-treated exhibit various senescence-associated phenotypes, but remain insensitive to common senolytic compounds. By searching for novel vulnerabilities, identified significantly increased lysosomal mass altered structure across cell types upon exposure CDK4/6i in preclinical systems clinical specimens. We demonstrated these alterations render sensitive lysosomotropic agents, such as L- leucyl-L-leucine methyl ester (LLOMe) salinomycin. Importantly, sequential with CDK4/6i/lysosomotropic agents effectively reduced both Hormone Receptor- positive (HR + ) triple-negative (TNBC) vivo. This therapeutic strategy offers promising approach eliminate CDK4/6i-induced senescent(-like) cells, potentially reducing tumor recurrence enhancing overall therapy.

Language: Английский

Citations

0