Biology subjects

Waters, A. M.

Publications and source records attributed to Waters, A. M..

4 recordsLinked to original sources

bioRxiv2026

Concurrent AXL inhibition enhances RAS and ERK inhibitor efficacy in KRAS-mutant pancreatic and lung cancer

Resistance limits the clinical efficacy of RAS inhibitors. We applied chemical and genetic screens and identified the AXL receptor tyrosine kinase as a driver of resistance to RAS-ERK inhibition. We determined that combination treatment with the AXL inhibitor bemcentinib (AXLi) together with the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 (RASi) or the ERK-selective inhibitor SCH772984 (ERKi) significantly enhanced growth suppression in human KRAS-mutant pancreatic and lung cancer models. Combined AXLi and RASi treatment of human KRAS-mutant pancreatic cell line-derived xenograft tumors synergistically suppressed ERK activation and MYC expression, and caused tumor regression. Analyses of immunocompetent mouse allograft pancreatic tumor models revealed a largely tumor cell-intrinsic response to inhibitor treatment. We identified an unexpected mechanism whereby KRAS inhibition upregulated the AXL ligand GAS6, activating AXL but inducing an AXL-dependent adaptive resistance mechanism wherein AXL antagonizes RASi efficacy. Our observations support concurrent AXL inhibition as a strategy to enhance RAS inhibitor clinical efficacy. STATEMENT OF SIGNIFICANCEOur findings identify AXL as a driver of resistance to RAS inhibitors, establishing a combination strategy to overcome resistance and enhance RAS inhibitor therapeutic efficacy in KRAS-mutant cancer by maximally inhibiting oncogenic RAS signaling.

cancer biology↗

bioRxiv2026

Characterization and therapeutic suppression of KEAP1-NRF2-driven resistance to KRAS inhibitors in pancreatic and lung cancer

The recent approval of KRAS inhibitors supports the therapeutic value of targeting mutant KRAS cancers. However, clinical efficacy is hindered by both primary and treatment-associated acquired resistance. We applied a CRISPR-Cas9 loss-of-function screen and identified loss of KEAP1 as a resistance mechanism to the KRASG12D-selective inhibitor MRTX1133 and the RAS(ON) multi-selective inhibitor RMC-7977 in pancreatic cancer models. RNA-sequencing analyses revealed a KEAP1KO transcriptome that is distinct from the ERK-, MYC-, and YAP/TAZ-TEAD-dependent transcriptional programs that drive KRAS inhibitor resistance, demonstrating a distinct mechanism of resistance. We then established a PDAC KEAP1-deficient (PKD) gene signature that was enriched in patients and preclinical models insensitive to KRAS inhibitor treatment. Finally, we observed that KEAP1-deficient cells exhibited elevated glutamine metabolism, and combination treatment with the glutamine antagonist DRP-104 (sirpiglenastat) enhanced KRAS inhibitor suppression of pancreatic and lung tumors. SIGNIFICANCEKEAP1 loss is associated with reduced response to KRAS inhibitor therapy. We demonstrate that KEAP1 loss-associated resistance can be overcome by pharmacologic inhibition of the KEAP1 loss-induced glutamine dependency, establishing a combination to enhance RAS inhibitor clinical efficacy.

cancer biology↗

bioRxiv2022

Exploration of single-cell transcriptomic landscape identifies aberrant glomerular crosstalk in a murine model of WT1 kidney disease

The glomerulus mediates kidney ultrafiltration through specialised epithelial cells called podocytes which line a basement membrane shared with blood capillary endothelium. Cell-cell crosstalk is critical for glomerular function, but its investigation in childhood glomerular diseases has received little attention. WT1 encodes a transcription factor expressed in podocytes, whose heterozygous variants cause devastating kidney disease in childhood. We used single-cell RNA sequencing and ligand-receptor interaction analysis to resolve the glomerular transcriptional landscape of mice that carry an orthologous human mutation in WT1 (Wt1R394W/+). Podocytes were the most dysregulated cell type in early disease, with disrupted angiogenic signalling preceding glomerular capillary loss. Comparative analyses with additional murine and human glomerular disease datasets identified unique transcriptional changes in WT1 glomerular disease, reflecting a non-immunological pathology, whilst revealing a common injury signature across multiple glomerular diseases. Collectively, this work advocates vascular-based therapies over immunosuppressive drugs in the treatment of WT1 glomerular disease.

cell biology↗

bioRxiv2022

Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this novel class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.

cancer biology↗