Biology subjects

Ke, E.

Publications and source records attributed to Ke, E..

4 recordsLinked to original sources

bioRxiv2026

Overcoming Daraxonrasib Resistance: Allele-Specific Mechanisms Guide Salvage Therapy in Pancreatic Cancer

Clinical-grade RAS inhibitors raise an unresolved question as to whether KRAS-alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multi-selective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, alleles with fundamentally different RAS network dynamics. Daraxonrasib inhibited KRASMUT primarily through steric occlusion of effector binding, while engaging RASWT only modestly ([~]20%). KRASG12R is marked by its inability to transactivate RASWT, and it was observed that daraxonrasib resistant KRASG12R PDAC cells utilize EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease of cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to the EGFR/RASWT conferred sensitivity to trametinib. We confirmed this clinically: a KRASG12R PDAC patient who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived toroid modeling predicted sensitivity to trametinib-based combination therapy. Given the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control. This patient ultimately achieved 40 months of overall survival, far exceeding the 8-12 month median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC. STATEMENT OF SIGNIFICANCEDaraxonrasib resistance mechanisms have allele-specific routes: CypA becomes downregulated in KRASG12D and reliance on EGFR/RASWT in KRASG12R. Rapid patient-derived toroids identified sixth-line targeted therapy strategies with an overall survival of 40 months.

cancer biology↗

bioRxiv2026

Existence of Causation without Correlation in Transcriptional Networks

It is commonly assumed that lack of correlation is evidence for lack of causal relationship. Here, however we show that in transcriptional networks, causal linkages can exist in the absence of correlation. We find that a substantial proportion of transcribed genes in yeast and in mouse, show evidence of state-dependent (nonlinear) and temporally coordinated dynamics in their expression patterns (65-77%). Using a test that accommodates this fact, we uncover strong causal relationships that are invisible to correlation-based analyses for both yeast and mouse models. Specifically, for yeast we detect uncorrelated causal relationships for the transcriptional regulators WHI5 and YHP1, and can verify these relationships experimentally. These genes reside at important checkpoints in the cell cycle where multiple signals are integrated at single nodes, giving rise to causal relationships, that despite being uncorrelated, can be accurately detected (71-78%) using a nonlinear causality test.

systems biology↗

bioRxiv2022

Delineate clonal dynamics of ovarian cancer initiating cells during pre-malignant progression using a mouse genetic mosaic system

Different cellular compartments within a tissue present distinct cancer-initiating capacities. Current approaches to delineate cancer-initiating heterogeneity require a well-understood lineage hierarchy and cell-specific genetic tools, which are lacking for many tissues. Here, we circumvented this hurdle and investigated the capacity of fallopian tube cells in initiating serous ovarian cancer, utilizing a mouse genetic system that generates scattered GFP-labeled mutant cells. Through quantitative tracing of clonal expansion of individual mutant cells, we revealed that only a rare primitive subset enriched in the distal fallopian tube is capable of clonal expansion whereas others stall immediately upon acquiring oncogenic mutations. Expanded clones from this subset then encountered further attrition: many stalled shortly after while others sustained small cluster of proliferative cells and biased differentiation toward primitive fate. Taken together, our study showcases quantitative clonal tracing as a powerful approach to investigate cancer-initiating heterogeneity and clonal trajectory in tissues with limited prior knowledge.

cancer biology↗

bioRxiv2021

PML-Dependent Memory of Type I Interferon Treatment Results in a Restricted Form of HSV Latency

Herpes simplex virus (HSV) establishes latent infection in long-lived neurons. During initial infection, neurons are exposed to multiple inflammatory cytokines but the effects of immune signaling on the nature of HSV latency is unknown. We show that initial infection of primary murine neurons in the presence of type I interferon (IFN) results in a form of latency that is restricted for reactivation. We also found that the subnuclear condensates, promyelocytic leukemia-nuclear bodies (PML-NBs), are absent from primary sympathetic and sensory neurons but form with type I IFN treatment and persist even when IFN signaling resolves. HSV-1 genomes colocalized with PML-NBs throughout a latent infection of neurons only when type I IFN was present during initial infection. Depletion of PML prior to or following infection did not impact the establishment latency; however, it did rescue the ability of HSV to reactivate from IFN-treated neurons. This study demonstrates that viral genomes possess a memory of the IFN response during de novo infection, which results in differential subnuclear positioning and ultimately restricts the ability of genomes to reactivate.

immunology↗