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PreprintCC BYbioRxiv

A therapeutic vulnerability linking MNK1/2 inhibition and G1/S cyclin-dependent kinase blockade in triple-negative breast cancer

  • Q. Deng
  • M. Amiri1
  • A. Moshari
  • B. Diddeniya
  • P. Akbarnia
  • A. A. Piric
  • E. Prando Munhoz
  • Y. Bagherian
  • Z. Li
  • M. A. Bellucci
  • N. Mahmood
  • M. Pollak
2 more authors
  • S. Huang
  • N. Sonenberg
  1. 1The Rockefeller University
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Abstract

Triple-negative breast cancer (TNBC) is a clinically challenging disease with limited therapeutic options. MAP kinase-interacting kinases 1 and 2 (MNK1/2)-mediated phosphorylation of eukaryotic initiation factor 4E (eIF4E) promotes oncogenic translation and represents a potential therapeutic target. We previously showed that loss of eIF4E phosphorylation suppresses metastasis but not primary tumor growth. Here, an shRNA screen surveying druggable genes unveiled cyclin-dependent kinase 4 (CDK4) as a genetic vulnerability to MNK1/2 inhibition in MDA-MB-231 TNBC cells. Although CDK4/6 inhibitors are approved for hormone receptor (HR)-positive, HER2-negative breast cancer, they are not approved for TNBC. We demonstrate that MNK1/2 inhibition synergizes with CDK4/6 blockade suppresses TNBC cell growth, a synergy also observed in another independent TNBC cell line (SUM159) using a broader G1/S CDK (CDK2/4/6) inhibitor. Integrated RNA sequencing and ribosome profiling revealed combination-specific changes in translation associated with mitotic checkpoint control and DNA repair. Our findings document MNK1/2 inhibition as a strategy to sensitize TNBC to G1/S CDK inhibition and provide a new avenue for therapeutic combination.

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Cite

BibTeXRIS
BibTeX
@misc{deng2026therapeutic,
  title = {{A therapeutic vulnerability linking MNK1/2 inhibition and G1/S cyclin-dependent kinase blockade in triple-negative breast cancer}},
  author = {Q. Deng and M. Amiri and A. Moshari and B. Diddeniya and P. Akbarnia and A. A. Piric and E. Prando Munhoz and Y. Bagherian and Z. Li and M. A. Bellucci and N. Mahmood and M. Pollak and S. Huang and N. Sonenberg},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.11.750258},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.11.750258v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - A therapeutic vulnerability linking MNK1/2 inhibition and G1/S cyclin-dependent kinase blockade in triple-negative breast cancer
AU  - Q. Deng
AU  - M. Amiri
AU  - A. Moshari
AU  - B. Diddeniya
AU  - P. Akbarnia
AU  - A. A. Piric
AU  - E. Prando Munhoz
AU  - Y. Bagherian
AU  - Z. Li
AU  - M. A. Bellucci
AU  - N. Mahmood
AU  - M. Pollak
AU  - S. Huang
AU  - N. Sonenberg
PY  - 2026
DA  - 2026/09/11
PB  - bioRxiv
DO  - 10.64898/2026.09.11.750258
UR  - https://www.biorxiv.org/content/10.64898/2026.09.11.750258v1
AB  - Triple-negative breast cancer (TNBC) is a clinically challenging disease with limited therapeutic options. MAP kinase-interacting kinases 1 and 2 (MNK1/2)-mediated phosphorylation of eukaryotic initiation factor 4E (eIF4E) promotes oncogenic translation and represents a potential therapeutic target. We previously showed that loss of eIF4E phosphorylation suppresses metastasis but not primary tumor growth. Here, an shRNA screen surveying druggable genes unveiled cyclin-dependent kinase 4 (CDK4) as a genetic vulnerability to MNK1/2 inhibition in MDA-MB-231 TNBC cells. Although CDK4/6 inhibitors are approved for hormone receptor (HR)-positive, HER2-negative breast cancer, they are not approved for TNBC. We demonstrate that MNK1/2 inhibition synergizes with CDK4/6 blockade suppresses TNBC cell growth, a synergy also observed in another independent TNBC cell line (SUM159) using a broader G1/S CDK (CDK2/4/6) inhibitor. Integrated RNA sequencing and ribosome profiling revealed combination-specific changes in translation associated with mitotic checkpoint control and DNA repair. Our findings document MNK1/2 inhibition as a strategy to sensitize TNBC to G1/S CDK inhibition and provide a new avenue for therapeutic combination.
ER  -