McGrath, C. | bioRxiv Science

bioRxiv2026

Incremental AMR acquisition driving successive genotype replacements and the rise of extensively drug resistant (XDR) Shigella sonnei in Australia over 20 years.

BackgroundIn Australia, the burden of shigellosis is predominantly in returning travellers or in men who have sex with men (MSM). Here, we combine genomic data with comprehensive epidemiological data on sexual exposure and international travel to explore population dynamics of Shigella sonnei and the expansion of multi-drug resistant (MDR) and extensively drug-resistant (XDR) sub-lineages. MethodsA population-level study of all cultured Shigella sonnei isolates in the state of Victoria, Australia, was undertaken between January 2002 and December 2024. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatic analyses of 1,305 Shigella sonnei isolates were performed at the Microbiological Diagnostic Unit Public Health Laboratory. Enhanced metadata on source attribution including travel and sexual exposure were collected through surveillance forms or by interviews. ResultsThis study highlights significant shifts in Shigella sonnei cases in Victoria from sensitive strains to MDR and then XDR, particularly in the MSM-associated groups but also associated with a large point source outbreak. We describe an historical pattern of shifting genotype prevalence, and replacement to more varied and higher proportions of antimicrobial resistance over the last decade, resulting in the establishment of two distinct but highly concerning XDR sub-lineages within Victoria. ConclusionsOur genomic-epidemiological analyses highlight that drug-resistant Shigella sonnei remains an ongoing public health threat, and the importance of ongoing surveillance. We determined local evolutionary trajectories and identified expanding sub-lineages that informed shifts in clinical management and antimicrobial recommendations over time, including the use of azithromycin and carbapenems. Placing these local dynamics within the broader global epidemiology, we link how regional evolution interconnects with international dissemination, proving valuable context for guiding local, national and global strategies for prevent outbreaks and antimicrobial resistance.

microbiology↗

bioRxiv2025

Co-targeting KRAS and Exportin1 as an effective therapeutic strategy for KRASG12D mutant pancreatic ductal adenocarcinoma

BackgroundSeveral KRASG12D inhibitors (KRASG12Di) are under clinical evaluation for pancreatic ductal adenocarcinoma (PDAC). However, as seen with other first generation KRAS inhibitors, resistance may limit their long-term efficacy, necessitating combination strategies to enhance therapeutic outcomes. Exportin 1 (XPO1), a nuclear transport protein overexpressed in PDAC, represents a therapeutic vulnerability in KRAS-mutant cancers. Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models. MethodsWe generated KRASG12Di-resistant PDAC cells and assessed their response to Eltanexor. The antiproliferative effects of MRTX1133 and Eltanexor combinations were evaluated in 2D and 3D in vitro PDAC models. The in vivo efficacy of the combination was tested in KRASG12D-mutant human and murine PDAC xenograft and allograft models. ResultsEltanexor sensitized MRTX1133-resistant PDAC cells to growth inhibition. In both 2D and 3D culture models, the combination of Eltanexor and MRTX1133 significantly reduced cell viability. Mechanistically, the combination treatment suppressed key KRAS downstream signaling molecules, including p-ERK, mTOR, p-4EBP1, DUSP6, and cyclin D1. Kinome analysis further revealed reduced MAPK-related kinase activity. Combining subtherapeutic doses of Eltanexor and MRTX1133 resulted in significant tumor regression and prolonged survival in PDAC xenograft and immunocompetent orthotopic allograft models. Moreover, maintenance therapy with Eltanexor prevented tumor relapse, yielding a durable antitumor response. ConclusionThis study demonstrates that Eltanexor overcomes resistance to MRTX1133 and enhances its efficacy in PDAC. The combination regimen may provide a durable therapeutic response while reducing the required dose of KRASG12D inhibitors, potentially delaying resistance and improving patient outcomes. Statement of Translational RelevancePDAC remains one of the deadliest malignancies, with limited effective therapies and dismal survival rates. The emergence of KRASG12D-selective inhibitors, such as MRTX1133, marks a critical advance for nearly 40% of PDAC patients harboring this oncogenic driver. However, inevitable emergence of adaptive or acquired resistance to KRAS inhibitors remains a major barrier to achieving durable clinical benefit. This study uncovers XPO1 inhibition as a rational and synergistic strategy to augment the antitumor efficacy of MRTX1133. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options.

cancer biology↗