Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition

Fassl, Anne; Brain, Christopher T.; Abu-Remaileh, Monther; Stukan, Iga; Butter, Deborah; Stępień, Piotr; Feit, Avery; Bergholz, Johann; Michowski, Wojciech; Otto, Tobias; Sheng, Qing; Loo, Alice; Michael, Walter; Tiedt, Ralph; Angelis, Carmine De; Schiff, Rachel; Jiang, Baishan; Jovanović, Bojana; Nowak, Karolina; Ericsson, Maria; Cameron, Michael D.; Gray, Nathanael S.; Dillon, Deborah; Zhao, Jean J.; Sabatini, David M.; Jeselsohn, Rinath; Brown, Myles; Polyák, Kornélia; Siciński, Piotr

doi:10.1126/sciadv.abb2210

Cited by 52 publications

(47 citation statements)

References 41 publications

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“…Once trapped inside endolysosome, weak-base chemotherapeutic drugs can no longer reach the cytosolic compartment and the nucleus to exert their anticancer effects; processes linked to chemoresistance ( Zhitomirsky and Assaraf, 2017 ). Such trapped weak-base chemotherapeutic drugs can directly alter endolysosome structure and function, such as alteration in endolysosome pH and influence endolysosome-dependent signaling that results in enhanced endolysosome biogenesis ( Fassl et al, 2020 ). Alternatively, trapped weak-base chemotherapeutic drugs can be eliminated from the cell via an increase in the lysosomal exocytosis cellular process, which is known to be directly due to these drugs themselves ( Hrabeta et al, 2020 ).…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine

Halcrow

Geiger

Chen

2021

Front. Cell Dev. Biol.

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Resistance to the anti-cancer effects of chemotherapeutic agents (chemoresistance) is a major issue for people living with cancer and their providers. A diverse set of cellular and inter-organellar signaling changes have been implicated in chemoresistance, but it is still unclear what processes lead to chemoresistance and effective strategies to overcome chemoresistance are lacking. The anti-malaria drugs, chloroquine (CQ) and its derivative hydroxychloroquine (HCQ) are being used for the treatment of various cancers and CQ and HCQ are used in combination with chemotherapeutic drugs to enhance their anti-cancer effects. The widely accepted anti-cancer effect of CQ and HCQ is their ability to inhibit autophagic flux. As diprotic weak bases, CQ and HCQ preferentially accumulate in acidic organelles and neutralize their luminal pH. In addition, CQ and HCQ acidify the cytosolic and extracellular environments; processes implicated in tumorigenesis and cancer. Thus, the anti-cancer effects of CQ and HCQ extend beyond autophagy inhibition. The present review summarizes effects of CQ, HCQ and proton pump inhibitors on pH of various cellular compartments and discuss potential mechanisms underlying their pH-dependent anti-cancer effects. The mechanisms considered here include their ability to de-acidify lysosomes and inhibit autophagosome lysosome fusion, to de-acidify Golgi apparatus and secretory vesicles thus affecting secretion, and to acidify cytoplasm thus disturbing aerobic metabolism. Further, we review the ability of these agents to prevent chemotherapeutic drugs from accumulating in acidic organelles and altering their cytosolic concentrations.

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Section: Tumor Microenvironmentmentioning

confidence: 99%

Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine

Halcrow

Geiger

Chen

2021

Front. Cell Dev. Biol.

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“…Nonetheless, our analyses implicated upregulation of PI3K signaling via a PIK3CA p.E542K activating mutation, compensatory feedback signaling through mTORC2, activation of CDK2, sequestration by lysosomotropism, and compensatory signaling via the androgen receptor as possible resistance mechanisms. These analyses support switching from palbociclib to abemaciclib to counter the observed CDK2 activation (Hafner et al, 2019), use of enzalutamide to counter possible androgen mediated signaling as was done in Phase 3, and administration of a lysosomotropic drug such as hydroxychloroquine (Fassl et al, 2020) to counter sequestration of palbociclib or abemaciclib. Phase 1 treatment was terminated when blood biomarkers and CT measurement of several-but not all-metastatic lesions began to increase sharply.…”

Section: Discussionmentioning

confidence: 64%

“…This mechanism is suggested by the increase in lysosomes from Bx1 to Bx2 revealed by FIB-SEM ( Figures 6G, S6A). Drug sequestration via lysosomotropism has been implicated as a mechanism of resistance to palbociclib and other CDK4/6 inhibitors, indicating a possible role for these abundant vesicles in reducing therapeutic efficacy in this patient (Fassl et al, 2020;Llanos et al, 2019).…”

Section: Activation Of Cdk2 and Drug Sequestration Via Lysosomotropismentioning

confidence: 99%

An Omic and Multidimensional Spatial Atlas from Serial Biopsies of an Evolving Metastatic Breast Cancer

Johnson

Creason

Stommel

et al. 2020

Preprint

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SummaryMetastatic cancers often respond to treatment initially but almost universally escape therapeutic control through molecular mechanisms intrinsic to tumor cells, as well as extrinsic influences from immune cells, stroma, and structural microenvironments. We explore the extent to which we can learn these mechanisms and associated therapeutic vulnerabilities by linking comprehensive molecular and multiscale imaging analyses of tumor biopsies to detailed clinical information for a patient with metastatic breast cancer. Our analyses of three serial biopsies include DNA, RNA, and protein profiling, plus quantification of tumor microenvironment composition using multiplex immunostaining and electron microscopy. Features from these analyses are linked to treatments and treatment-response measurements, including CT and PET images, circulating tumor DNA and tumor protein levels in blood, and treatment-limiting readouts of blood counts and liver function. Importantly, the measurement modalities unique to this study complemented routine diagnostics to suggest actionable mechanisms of response and resistance for each treatment phase.

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“…In line with this, patients with FAT1-deficient tumors displayed a significantly shortened PFS compared to patients with FAT1-proficient tumors. Furthermore, a study by Cornell et al reported an increased expression of CDK6 being elicited by suppression of the TGF-β pathway via exosomal miRNA 432-5p [ 98 ].…”

Section: Other Mechanisms Of Cdk4/6 Inhibitor Resistancementioning

confidence: 99%

“…Finally, in triple-negative breast cancer (TNBC), an increased number of tumor cell lysosomes has been shown to mediate the intrinsic resistance to CDK4/6 inhibition [ 98 ]. Driven by their weak base properties, CDK4/6 inhibitors are sequestered into the enlarged lysosomal compartment and, therefore, are hindered from reaching their target, i.e., cyclin D-CDK4/6 complexes in the nucleus.…”

Section: Other Mechanisms Of Cdk4/6 Inhibitor Resistancementioning

confidence: 99%

Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer

Sobhani

Fassl

Mondani

et al. 2021

Cells

Self Cite

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Breast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)—in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated.

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Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition

Cited by 52 publications

References 41 publications

Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine

Overcoming Chemoresistance: Altering pH of Cellular Compartments by Chloroquine and Hydroxychloroquine

An Omic and Multidimensional Spatial Atlas from Serial Biopsies of an Evolving Metastatic Breast Cancer

Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer

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