CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity

Watt, April C.; Cejas, Paloma; DeCristo, Molly J.; Metzger‐Filho, Otto; Lam, Enid Y.N.; Qiu, Xintao; BrinJones, Haley; Kesten, Nikolas; Coulson, Rhiannon; Font-Tello, Alba; Lim, Klothilda; Vadhi, Raga; Daniëls, Veerle W.; Montero, Joan; Taing, Len; Meyer, Clifford A.; Gilan, Omer; Bell, Charles C.; Korthauer, Keegan; Giambartolomei, Claudia; Paşaniuc, Bogdan; Seo, Ji Heui; Freedman, Matthew L.; Ma, Cynthia; Ellis, Matthew J.; Krop, Ian E.; Winer, Eric P.; Letaï, Anthony; Brown, Myles; Dawson, Mark A.; Long, Henry W.; Zhao, Jean J.; Goel, Shom

doi:10.1038/s43018-020-00135-y

Cited by 61 publications

(47 citation statements)

References 63 publications

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“…Both SOX10 and MITF were significantly downregulated in the PD-L1 CON cells, along with a dedifferentiation gene expression profile and increased expression of RTK genes which highlights the importance of PD-L1 CON expression during adaptive drug resistance. Moreover, TFs that were significantly upregulated consisted of AP-1 ( JUN and FOSL2 ), which have recently been shown to not only mediate the TNF signalling pathways, but also to alter the transcriptional and enhancer chromatin landscape by serving as pioneer TFs [ 58 , 59 , 60 ]. Transcriptomic reprogramming and differentiation often involves pioneer TFs, which facilitate and alter access to distinct regulatory elements, and consequently alter the chromatin landscape [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways

Ahn

Rodger

Motwani

et al. 2021

Cancers

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Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved the survival of melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to targeted therapy is associated with transcriptomic changes and has also been shown to be accompanied by increased expression of programmed death ligand 1 (PD-L1), a potent inhibitor of immune response. Intrinsic upregulation of PD-L1 is associated with genome-wide DNA hypomethylation and widespread alterations in gene expression in melanoma cell lines. However, an in-depth analysis of the transcriptomic landscape of melanoma cells with intrinsically upregulated PD-L1 expression is lacking. To determine the transcriptomic landscape of intrinsically upregulated PD-L1 expression in melanoma, we investigated transcriptomes in melanomas with constitutive versus inducible PD-L1 expression (referred to as PD-L1CON and PD-L1IND). RNA-Seq analysis was performed on seven PD-L1CON melanoma cell lines and ten melanoma cell lines with low inducible PD-L1IND expression. We observed that PD-L1CON melanoma cells had a reprogrammed transcriptome with a characteristic pattern of dedifferentiated gene expression, together with active interferon (IFN) and tumour necrosis factor (TNF) signalling pathways. Furthermore, we identified key transcription factors that were also differentially expressed in PD-L1CON versus PD-L1IND melanoma cell lines. Overall, our studies describe transcriptomic reprogramming of melanomas with PD-L1CON expression.

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Section: Discussionmentioning

confidence: 99%

Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways

Ahn

Rodger

Motwani

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Both SOX10 and MITF were significantly downregulated in the PD-L1CON cells, along with a dedifferentiation gene expression profile and increased expression of RTK genes which highlights the importance of PD-L1CON expression during adaptive drug resistance. Moreover, TFs that were significantly upregulated consisted of AP-1 (JUN and FOSL2) which have recently been shown to, not only mediate the TNF signalling pathways, but also to alter the transcriptional and enhancer chromatin landscape, by serving as pioneer TFs [57][58][59]. Transcriptomic reprogramming and differentiation often involves pioneer TFs, which facilitate and alter access to distinct regulatory elements, and consequently alter the chromatin landscape [60].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional reprogramming and constitutive PD-L1 expression in melanoma are associated with dedifferentiation and activation of interferon and tumor necrosis factor signaling pathways

Ahn

Rodger

Gimenez

et al. 2021

Preprint

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Melanoma is the most aggressive type of skin cancer, with increasing incidence worldwide. Advances in targeted therapy and immunotherapy have improved the survival of melanoma patients experiencing recurrent disease, but unfortunately treatment resistance frequently reduces patient survival. Resistance to targeted therapy is associated with transcriptomic changes, and has also been shown to be accompanied by increased expression of programmed death ligand 1 (PD-L1), a potent inhibitor of immune response. Intrinsic upregulation of PD-L1 is associated with genome-wide DNA hypomethylation and widespread alterations in gene expression in melanoma cell lines. However, an in-depth analysis of the transcriptomic landscape of melanoma cells with intrinsically upregulated PD-L1 expression is lacking. To determine the transcriptomic landscape of intrinsically upregulated PD-L1 expression in melanoma, we investigated tran-scriptomes in melanomas with constitutive versus inducible PD-L1 expression (referred to as PD-L1CON and PD-L1IND). RNA-Seq analysis was performed on seven PD-L1CON melanoma cell lines and ten melanoma cell lines with low inducible PD-L1IND expression. We observed that PD-L1CON melanoma cells had a reprogrammed transcriptome with a characteristic pattern of dedifferentiated gene expression, together with active interferon (IFN) and tumor necrosis factor (TNF) signalling pathways. Furthermore, we identified key transcription factors that were also differentially expressed in PD-L1CON versus PD-L1IND melanoma cell lines. Overall, our studies describe transcriptomic reprogramming of melanomas with PD-L1CON expression.

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“…Similarly, Watt and colleagues observed that breast cancer cell lines and PDX models treated with the CDK4/6i abemaciclib or palbociclib, displayed a remodeling of the chromatin architecture with a wide activation of transcription enhancers and super-enhancers. These transcriptional modifications are involved in the regulation of luminal differentiation, apoptosis and immune response [ 29 ]. Whether these activities of CDK4/6i are due to unexpected off target effects of the inhibitors or effectively to the inhibition of CDK4 and/or CDK6 kinases activities, although largely expected, has not been formally demonstrated [ 29 ].…”

Section: Non-cell Cycle Dependent Activities Of Cdk4 and Cdk6mentioning

confidence: 99%

“…These transcriptional modifications are involved in the regulation of luminal differentiation, apoptosis and immune response [ 29 ]. Whether these activities of CDK4/6i are due to unexpected off target effects of the inhibitors or effectively to the inhibition of CDK4 and/or CDK6 kinases activities, although largely expected, has not been formally demonstrated [ 29 ].…”

Section: Non-cell Cycle Dependent Activities Of Cdk4 and Cdk6mentioning

confidence: 99%

Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives

Dall'Acqua

Bartoletti

Masoudi-Khoram

et al. 2021

Cancers

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Alterations in components of the cell-cycle machinery are present in essentially all tumor types. In particular, molecular alterations resulting in dysregulation of the G1 to S phase transition have been observed in almost all human tumors, including ovarian cancer. These alterations have been identified as potential therapeutic targets in several cancer types, thereby stimulating the development of small molecule inhibitors of the cyclin dependent kinases. Among these, CDK4 and CDK6 inhibitors confirmed in clinical trials that CDKs might indeed represent valid therapeutic targets in, at least some, types of cancer. CDK4 and CDK6 inhibitors are now used in clinic for the treatment of patients with estrogen receptor positive metastatic breast cancer and their clinical use is being tested in many other cancer types, alone or in combination with other agents. Here, we review the role of CDK4 and CDK6 complexes in ovarian cancer and propose the possible use of their inhibitors in the treatment of ovarian cancer patients with different types and stages of disease.

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CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity

Cited by 61 publications

References 63 publications

Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways

Transcriptional Reprogramming and Constitutive PD-L1 Expression in Melanoma Are Associated with Dedifferentiation and Activation of Interferon and Tumour Necrosis Factor Signalling Pathways

Transcriptional reprogramming and constitutive PD-L1 expression in melanoma are associated with dedifferentiation and activation of interferon and tumor necrosis factor signaling pathways

Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives

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