A selective inhibitor of oncogenic JNK signalling perturbs metastatic outgrowth of triple-negative breast cancer through metabolic blockade

  1. Sharissa L Latham
  2. Yolande EI O’Donnell
  3. Oscar Girgis-Cook
  4. Misaki S Clearwater
  5. Nicole S Bryce
  6. Ellie TY Mok
  7. Sophie A Lynn
  8. Jenny Ni
  9. Stephanie Alfred
  10. King Ho Leong
  11. Lake-ee Quek
  12. Kendelle J Murphy
  13. Chiara Pantarelli
  14. Iliya Dragutinovic
  15. Marjan M Naeini
  16. Claudia Thiel
  17. Antonia Cadell
  18. Monica Phimmachanh
  19. Rashmi Sharma
  20. Ewan Millar
  21. Jeremy ZR Han
  22. Jordan F Hastings
  23. Martin Köhler
  24. Tilman Brummer
  25. Adelaide Young
  26. Sandra O’Toole
  27. Samantha R Oakes
  28. Edna Hardeman
  29. John Lock
  30. Walter Kolch
  31. Manuel H Taft
  32. Max Nobis
  33. Leonard Goldstein
  34. Paul Timpson
  35. Benjamin L Parker
  36. Jeff Holst
  37. Peter W Gunning
  38. Thomas R Cox
  39. Jonathan C Morris
  40. David R Croucher
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Abstract

Although c-Jun N-terminal Kinase (JNK) represents an attractive anti-cancer target, its pleiotropic functionality limits the use of direct JNK inhibitors. Here, we identify a distinct subcellular pattern of JNK activity as a therapeutic vulnerability in breast cancer, where cytoplasmic JNK activity predicts poor survival outcomes, is elevated in triple-negative breast cancers (TNBC) and is essential for metastatic outgrowth. Mechanistic analyses reveal cytoplasmic JNK acts through multiple mechanisms, with downstream targets involved in cellular metabolism and cytoskeletal regulation. On this basis, we leveraged actin-based phenotypic drug-screening and identified K12, an indirect but selective inhibitor of cytoplasmic JNK that blocks TNBC metastatic outgrowthin vivo. We reveal that K12 inhibits glutaminase-1 and the pyruvate dehydrogenase complex, and that this poly-pharmacology overcomes pyruvate anaplerosis, a known resistance mechanism of existing glutaminase inhibitors. These findings demonstrate the potential of selectively targeting the oncogenic function of JNK, offering new treatment options for early-stage metastatic TNBC.

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