Poster Presentation 37th Lorne Cancer Conference 2025

Assessing KRAS inhibitors in pancreatic cancer using multiomics and advanced imaging to identify novel treatment co-targets (#262)

Victoria M Tyma 1 2 , Katie Gordon 1 2 , Shona C Ritchie 1 2 , Kendelle J Murphy 1 2 , Australian Pancreatic Genome Initiative (APGI) 1 , Australian Pancreatic Cancer Matrix Atlas (APMA) 1 , David Herrmann 1 2 , Brooke A Pereira 1 2 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

Pancreatic cancer (PC) is one of the deadliest cancers, being the fourth leading cause of cancer related deaths in Australia1. During PC development, there are very few symptoms and no reliable early detection methods, resulting in most patients being initially diagnosed with advanced and/or metastatic PC. Due to this, most patients are not eligible for surgical resection of the tumour and thus receive systemic chemotherapy as standard-of-care. Unfortunately, PC usually rapidly develops chemoresistance, highlighting the need for specific and targeted options to better treat this highly aggressive malignancy.

In PC, mutation in the KRAS gene is present in >90% of patients2. Point mutations at codon 12 are most prevalent, particularly G12D (49.5% of cases)3. For this reason, KRAS has always been an attractive target in PC, although, up until recently, was considered ‘undruggable’. However, in the past few years, there has been a major medical advancement in developing highly effective and specific KRAS G12D inhibitors. For example, Mirati’s G12D KRAS inhibitor, MRTX1133, can cause a >50% decrease in tumour burden in mouse models of PC4. More broadly, pan-KRAS inhibitors can act on all KRAS mutations, such as RMC-6236 (Revolution Medicines) and BI-2493 (Boehringer Ingelheim)5,6. Despite these exciting results, it is likely that tumours will eventually become resistant to KRAS inhibition7, as is often the case with targeted therapies. Thus, we aim to analyse the effect of KRAS inhibition on the transcriptome, secretome and exosome profiles of pancreatic cancer cells, with an overarching goal to find new co-targets that can be drugged in combination with KRAS inhibitors to enhance therapy outcomes.

Ongoing work includes using RNAseq and mass spectrometry-based proteomics to assess the transcriptome as well as the secretome and exosomal cargo of syngeneic pancreatic cancer lines derived from the KPC mouse model of PC under pharmacological KRAS inhibition. Future work will also include assessment of our new putative co-targets using intravital (in vivo) imaging and biosensor technology.  Overall, we aim to find new targets for combination treatment to improve the efficacy and durability of these first-in-class KRAS inhibitors.

  1. Siegel, R. L., Giaquinto, A. N. & Jemal, A. Cancer statistics, 2024. CA: A Cancer Journal for Clinicians 74, 12-49, doi:https://doi.org/10.3322/caac.21820 (2024).
  2. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47-52, doi:10.1038/nature16965 (2016).
  3. Bournet, B. et al. KRAS G12D Mutation Subtype Is A Prognostic Factor for Advanced Pancreatic Adenocarcinoma. Clinical and Translational Gastroenterology 7, e157, doi:10.1038/ctg.2016.18 (2016)
  4. Kemp, S. B. et al. Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer. Cancer Discovery 13, 298-311, doi:10.1158/2159-8290.Cd-22- 1066 (2023).
  5. Jiang, J. et al. Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discovery 14, 994-1017, doi:10.1158/2159-8290.Cd-24-0027 (2024).
  6. Kim, D. et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature 619, 160–166, doi: 10.1038/s41586-023-06123-3 (2023)
  7. Dilly, J. Et al. Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer. Cancer Discovery, doi: 10.1158/2159-8290.CD-24-0177 (2024) Epub ahead of print.