Poster Presentation 35th Lorne Cancer Conference 2023

Understanding cellular mechanisms involved in drug response to gp130/STAT3 inhibitors in combination with chemotherapy in colorectal cancer (#134)

Rhynelle Dmello 1 , Michelle Palmieri 2 , Pathum Thilakasiri 1 , Larissa Doughty 3 , Tracy Nero 3 , Michael Parker 3 , Ivan Poon 4 , Eduard Batlle 5 , Matthias Ernst 1 , Ashwini Chand 1
  1. Olivia Newton John Cancer Research Institute and School of Cancer Medicine, La Trobe Univeristy, Melbourne, VIC, Australia
  2. Walter and Eliza Hall Insitute of Medical Research (WEHI), Melbourne, VIC, Australia
  3. Department of Biochemistry and Molecular Biology, Bio21 Institute, The University of Melbourne and ACRF Rational Drug Discovery Centre, St Vincent's Institute, Melbourne, VIC, Australia
  4. Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  5. Institute for Research in Biomedicine, Barcelona, Spain

Inflammatory cytokines, such as interleukin-6 (IL-6) and IL-11, activate the signal transducer and activator of transcription 3 (STAT3), which drives the gene transcription of cellular processes attributed as hallmarks of cancer. High levels of these cytokines in combination with driver mutations contribute to disease progression and poor survival outcomes in patients with colorectal cancer. Previous studies in our laboratory identified bazedoxifene (BZA) as a small molecule inhibitor of gp130 (the receptor common to the IL-6 family of cytokines), selectively suppressing IL-6 and IL-11 signalling reduce colon and gastric tumour growth in vivo (Thilakasiri et al, EMBO Mol Med 2019).

The aim of this study is to understand the cellular mechanisms that are impacted in response to gp130/STAT3 inhibition to mediate anti-tumour effects in colorectal cancer. Additionally, we also determined the combined effects of BZA in combination with standard of care chemotherapy and SMAC mimetics on pro-apoptotic signalling pathways and developed a proteomics signature to predict drug response to these treatment combinations in colorectal cancer.

Using patient-derived organoids from the sigmoid and ascending colon of stage II and III patients, the combined efficacy of BZA and chemotherapy (5-fluorouracil, oxaliplatin and the active metabolite of irinotecan-SN38) as well as BZA and SMAC mimetics (LCL-161 and Birnipant) were assessed using drug synergy assays. The effects of these drug combinations on pro-apoptotic pathways were also analysed using flow cytometry and dot protein arrays. Additionally, molecular pathways impacted in response to gp130/STAT3 inhibition (pharmacological and short hairpin mediated knock down) were assessed using reverse phase protein arrays.

Our results demonstrate that BZA treatment targets multiple hallmarks of cancer via multipronged effects on cancer cell signalling pathways, cell proliferation, apoptosis, DNA damage repair and epithelial-mesenchymal transition. BZA treatment sensitized colorectal cancer cells and patient derived organoids to chemotherapy treatment and SMAC mimetics leading to a potent increase in pro-apoptotic responses. Our findings suggest that BZA treatment could be used as an adjuvant to boost the effects of standard of care chemotherapy in patients where tumour growth is dependent on gp130/STAT3 signalling.