Oral Presentation 37th Lorne Cancer Conference 2025

Selective inhibition of oncogenic JNK signaling perturbs the outgrowth of triple negative breast cancer lung metastases (113518)

Sharissa L Latham 1 2 , Yolande O'Donnell 1 , Oscar Girgis-Cook 3 , Nicole Bryce 4 , Sophie Lynn 1 , Jenny Ni 1 , Misaki Clearwater 1 , King Leong 1 , Ellie Mok 1 , Chiara Pantarelli 1 , Iliya Dragutinovic 3 , Antonia Cadell 1 , Monica Phimmachanh 1 , Stephanie Alfred 1 , Jeremy ZR Han 1 , Jordan Hastings 3 , Anna Pahlman 1 , Boaz Ng 1 , Kendelle Murphy 1 2 , Melrine Pereira 5 , Kate Harvey 1 , Adelaide Young 1 , Sandra O'Toole 1 , Kara Britt 5 , Alex Swarbrick 1 2 , Samantha Oakes 1 , Edna Hardeman 4 , John Lock 4 , Max Nobis 1 2 , Paul Timpson 1 2 , Benjamin L Parker 6 , Jeff Holst 7 , Peter W Gunning 4 , Thomas R Cox 1 2 , Jonathan C Morris 3 , David R Croucher 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, UNSW, Darlinghurst, NSW, Australia
  3. School of Chemistry, UNSW Sydney, Kensington, NSW, Australia
  4. School of Medical Sciences, UNSW, Kensington, NSW, Australia
  5. Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia
  6. Department of Anatomy and Physiology, University of Melbourne, Melbourne, VIC, Australia
  7. School of Biomedical Sciences, UNSW Sydney, Kensington, NSW, Australia

Triple negative breast cancer (TNBC) patients have the worst outcomes of all breast cancer subtypes due to a lack of targeted therapies and high relapse rates with distant metastases. Given that metastases are the cause of death for the majority of these patients, there is an urgent need for the development of innovative approaches that specifically treat metastatic TNBC to improve patient outcomes.

The c-Jun N-terminal Kinase (JNK) has been identified as a central oncogenic signalling node in TNBC crucial for metastatic disease progression, making it an attractive therapeutic target. However, as JNK is also required to maintain the architecture of normal breast tissue and activate apoptosis in response to chemotherapeutic intervention, it is unlikely that broad-spectrum JNK inhibitors will yield clinical success. As such, alternate approaches are needed to selectively target the oncogenic functions of JNK.

Here, we show that oncogenic JNK activity in breast cancer is driven by a distinct cytoplasmic pool that is prognostic of poor survival outcomes, elevated in TNBC patients and essential for TNBC metastatic outgrowth. Off the basis of phosphoproteomics and morphological analyses, we have leveraged actin-based phenotypic drug screening and identified K12, a selective-inhibitor of cytoplasmic, oncogenic JNK signalling that blocks TNBC metastatic outgrowth in vivo. Further, we demonstrate that K12 elicits its effects by binding and inhibiting critical metabolic regulators. Our study is the first to attribute JNKs oncogenic functions in breast tissue to a discrete subcellular compartment and demonstrate that select downstream functions of JNKs can be therapeutically targeted, opening up novel treatment options for early-stage metastatic TNBC.