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Background <p>Polo-like kinase 4 (PLK4) is a key regulator of centriole duplication and contributes to mitotic spindle organization during cell division. PLK4 has been implicated as pharmacological target in a subset of breast cancers and neuroblastomas harboring 17q chromosomal gains and overexpression of the E3 ubiquitin-protein ligase TRIM37. Here, we investigated factors that influence sensitivity of cancer cells to PLK4 inhibition.</p> Methods <p>We used cBio Cancer Genomics Portal and DepMap portal and performed bioinformatic analysis of copy number variations and gene expression to identify potential pharmacologically targetable genes in invasive breast carcinoma with 17q gains. Subsequently, we tested sensitivity of cancer cells to combinations of PLK4 inhibitor with other small molecule compounds and determined the impact on cell proliferation, cell death and gene expression. Validation was performed using a chemically unrelated PLK4 inhibitor, by RNAi-mediated depletion of PLK4 and in <i>TP53</i> knock-out cells.</p> Results <p>We show that sensitivity of breast cancer cells with 17q23 amplification to PLK4 inhibitor is limited by the activity of protein phosphatase PPM1D, an established negative regulator of the tumor suppressor p53. Combined inhibition of PLK4 and PPM1D stimulates the expression of p53 target genes and promotes apoptosis in breast cancer cells with 17q gains. Similarly, combined inhibition of MDM2 and PLK4 was synthetically lethal in breast cancer cells with 17q gains, whereas loss of p53 suppressed the cell death induced by PLK4 inhibition. Finally, we show that PLK4 and PPM1D or MDM2 are synthetically lethal targets in IMR-32 and CHP-134 neuroblastoma cells, confirming that targeting negative regulators of p53 enhances the efficiency of the PLK4 inhibitor in various cancers with 17q amplification.</p> Conclusions <p>Our findings demonstrate that the combined inhibition of PLK4 and PPM1D or MDM2 sensitizes breast cancers and neuroblastoma with 17q gains and provide a rationale for advancing this novel drug combination into future preclinical development.</p>

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Combined inhibition of PLK4 and PPM1D promotes cell death in cancer cells with 17q amplification

  • 期刊论文

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  • 发表日期：

    2026年6月18日

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  • Miroslav Stoyanov,
  • Cecilia Aquino-Perez,
  • Shreyasi Mazumder,
  • Dominika Salcakova,
  • Silvia Petrezselyova,
  • Libor Macurek

摘要

Background

Polo-like kinase 4 (PLK4) is a key regulator of centriole duplication and contributes to mitotic spindle organization during cell division. PLK4 has been implicated as pharmacological target in a subset of breast cancers and neuroblastomas harboring 17q chromosomal gains and overexpression of the E3 ubiquitin-protein ligase TRIM37. Here, we investigated factors that influence sensitivity of cancer cells to PLK4 inhibition.

Methods

We used cBio Cancer Genomics Portal and DepMap portal and performed bioinformatic analysis of copy number variations and gene expression to identify potential pharmacologically targetable genes in invasive breast carcinoma with 17q gains. Subsequently, we tested sensitivity of cancer cells to combinations of PLK4 inhibitor with other small molecule compounds and determined the impact on cell proliferation, cell death and gene expression. Validation was performed using a chemically unrelated PLK4 inhibitor, by RNAi-mediated depletion of PLK4 and in TP53 knock-out cells.

Results

We show that sensitivity of breast cancer cells with 17q23 amplification to PLK4 inhibitor is limited by the activity of protein phosphatase PPM1D, an established negative regulator of the tumor suppressor p53. Combined inhibition of PLK4 and PPM1D stimulates the expression of p53 target genes and promotes apoptosis in breast cancer cells with 17q gains. Similarly, combined inhibition of MDM2 and PLK4 was synthetically lethal in breast cancer cells with 17q gains, whereas loss of p53 suppressed the cell death induced by PLK4 inhibition. Finally, we show that PLK4 and PPM1D or MDM2 are synthetically lethal targets in IMR-32 and CHP-134 neuroblastoma cells, confirming that targeting negative regulators of p53 enhances the efficiency of the PLK4 inhibitor in various cancers with 17q amplification.

Conclusions

Our findings demonstrate that the combined inhibition of PLK4 and PPM1D or MDM2 sensitizes breast cancers and neuroblastoma with 17q gains and provide a rationale for advancing this novel drug combination into future preclinical development.