In vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in human chordoma xenografts

Passeri, Thibault; Dahmani, Ahmed; Masliah‐Planchon, Julien; Botty, Rania El; Courtois, Laura; Vacher, Sophie; Marangoni, Elisabetta; Némati, Fariba; Roman‐Roman, Sergio; Adle‐Biassette, Homa; Mammar, Hamid; Froelich, Sébastien; Bièche, Ivan; Decaudin, Didier

doi:10.3389/fonc.2022.960720

Cited by 8 publications

(4 citation statements)

References 74 publications

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“…These results indicated that LRPPRC was also involved in regulating CDK4/6i sensitivity, beyond controlling CDK6 expression. The most studied functions of LRPPRC are promoting OXPHOS and cancer stem cells (CSCs) 24 , 40 , both of which have been shown to promote CDK4/6i resistance in some cancer types other than LUAD, such as glioma and bladder cancer 41 – 44 . Our results showed significantly increased expression of LRPPRC and OXPHOS after acquired CDK4/6i resistance in LUAD cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer

et al. 2023

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Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.

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Section: Resultsmentioning

confidence: 99%

The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer

et al. 2023

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“…However, considering the limited case number and retrospective nature of this report, the evidence level of this result is relatively low. Besides, as there is a paucity of feasible biomarkers for the evaluation of CDK4/6 inhibitor sensitivity in chordoma (Passeri et al 2022 ), another limitation of this research includes that the criteria for application of Palbociclib in the current case might be controversial. Hence, the precise prediction of Palbociclib sensitivity might be undermined, and the spatial heterogeneity of the tumor cannot be completely ruled out, which possibly lead to the reduced duration of treatment response.…”

Section: Discussionmentioning

confidence: 99%

“…Alterations of CDKN2A/2B, are known to play essential tumor-suppressing roles in a variety of tumors,, making this pathway an attractive therapeutic target (Helsten et al 2016 ; Kato et al 2015 ). Previous studies suggested that chordoma cells exhibiting a loss of CDKN2A (p16) may trigger universal activation of CDK4/6, implying the potential applicability of CDK4/6 inhibitor in chordoma treatment (Liu et al 2018 ) (Passeri et al 2022 ). However, no clinical evidence has ever been reported for the effectiveness of CDK inhibitors in the treatment of chordoma.…”

Section: Introductionmentioning

confidence: 99%

A retrospective study on the mechanism underlying quick transfer from response to resistance in a repeated recurrent chordoma patient with molecular alterations treated with Palbociclib

Zhong,

Yu,

Yang

et al. 2024

J Cancer Res Clin Oncol

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Purpose There is no approved targeted therapy for chordoma at present. Although several preclinical studies have implied the potential applicability of CDK4/6 inhibitor for this rare tumor, no clinical evidence has been documented so far. The purpose of this study was to elucidate the therapeutic efficacy of CDK4/6 inhibitor for chordoma. Methods The next generation sequencing (as for whole-exome sequencing, WES assay) and immunohistochemical (IHC) staining of the chordoma tissue from a patient with an advanced lesion were performed before treatment. Then, the patient was treated with Palbociclib for 4 months until progression occurred in the 5th month. Surgical resection was implemented and the tumor tissue was obtained postoperatively for assessment of molecular alterations. Results Molecular features of the tumor before medical treatment suggested applicability of CDK4/6 inhibitor and the patient showed partial response (PR) according to Choi Criteria after 4 months treating with Palbociclib until progression occurred. Then, a drastic molecular alteration of the tumor as represented by emergence of dramatic E2F amplification, which is known to induce CDK4/6 independent cell-cycle entry and progression after treatment, was detected. The findings in this patient demonstrated tumor evolution under drug pressure. Conclusion The findings of the present study suggest the feasibility of Palbociclib for the clinical treatment of chordoma, and imply the necessity of combination therapies rather single drug administration due to the quick resistance of the tumor to Palbociclib treatment.

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“…In turn, the role of cell cycle regulation and deletion of CDKN2A in chordoma C suggests an efficiency of cell cycle targeting therapy in these patients. Inhibitor of cyclin-dependent kinases 4/6, palbociclib showed an inhibitory activity in chordoma cell lines with P16/INK4A loss [ 60 ] and more recently in 1 (out of 2) chordoma xenografts with this 9p deletion [ 61 ]. The synergistic effect of combination of rapamycin and palbociclib in chordoma cell lines with PTEN and P16/INK4A loss was also shown [ 62 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment

Baluszek

Kober

Rusetska

et al. 2023

acta neuropathol commun

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Chordomas are rare tumors of notochord remnants, occurring mainly in the sacrum and skull base. Despite of their unusually slow growth, chordomas are highly invasive and the involvement of adjacent critical structures causes treatment challenges. Due to the low incidence, the molecular pathogenesis of this entity remains largely unknown. This study aimed to investigate DNA methylation abnormalities and their impact on gene expression profiles in skull base chordomas. 32 tumor and 4 normal nucleus pulposus samples were subjected to DNA methylation and gene expression profiling with methylation microarrays and RNA sequencing. Genome-wide DNA methylation analysis revealed two distinct clusters for chordoma (termed subtypes C and I) with different patterns of aberrant DNA methylation. C Chordomas were characterized by general hypomethylation with hypermethylation of CpG islands, while I chordomas were generally hypermethylated. These differences were reflected by distinct distribution of differentially methylated probes (DMPs). Differentially methylated regions (DMRs) were identified, indicating aberrant methylation in known tumor-related genes in booth chordoma subtypes and regions encoding small RNAs in subtype C chordomas. Correlation between methylation and expression was observed in a minority of genes. Upregulation of TBXT in chordomas appeared to be related to lower methylation of tumor-specific DMR in gene promoter. Gene expression-based clusters of tumor samples did not overlap with DNA methylation-based subtypes. Nevertheless, they differ in transcriptomic profile that shows immune infiltration in I chordomas and up-regulation of cell cycle in C chordomas. Immune enrichment in chordomas I was confirmed with 3 independent deconvolution methods and immunohistochemistry. Copy number analysis showed higher chromosomal instability in C chordomas. Nine out of eight had deletion of CDKN2A/B loci and downregulation of genes encoded in related chromosomal band. No significant difference in patients’ survival was observed between tumor subtypes, however, shorter survival was observed in patients with higher number of copy number alterations.

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In vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in human chordoma xenografts

Cited by 8 publications

References 74 publications

The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer

The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer

A retrospective study on the mechanism underlying quick transfer from response to resistance in a repeated recurrent chordoma patient with molecular alterations treated with Palbociclib

DNA methylation, combined with RNA sequencing, provide novel insight into molecular classification of chordomas and their microenvironment

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