Biology subjects

Hong, D. S.

Publications and source records attributed to Hong, D. S..

4 recordsLinked to original sources

bioRxiv2026

Concurrent Stereotactic Body Radiation Therapy and KRAS Inhibition Synergistically Improve Pre-clinical Pancreatic Cancer Treatment

Pancreatic ductal adenocarcinoma (PDAC) is one of the most challenging cancers to treat due to the dismal survival rate, poor post-treatment outcome and profound resistance to a wide range of therapies. With mutant KRAS being a key driver, small molecule inhibitors targeting KRAS or pan-RAS (KRASi) have demonstrated exciting preclinical and early clinical anti-tumor efficacy, and the pan-RAS(ON) inhibitor daraxonrasib (RMC-6236) recently achieved Phase 3 clinically meaningful improvements in patient survival compared to chemotherapy. But resistance to RAS/KRAS inhibitor inevitably develops, which limits and compromises the treatment outcome. In this study, we investigated the combination of stereotactic body radiation therapy (SBRT) and KRAS inhibition (MRTX1133 and daraxonrasib) in the treatment of preclinical PDAC models. We found that this combination strategy synergistically suppresses PDAC cell growth in vitro and enhances tumor control while minimizing local recurrence in orthotopically implanted KPC (LSL-KrasG12D/+;Trp53R172H/+;Pdx1-Cre) murine PDAC tumors in vivo. As radiation therapy (RT) induces ferroptosis in multiple cancer types and mutant KRAS promotes various anti-ferroptotic mechanisms, we tested the role of ferroptosis in promoting tumor-control efficacy. Intriguingly, the addition of a ferroptosis inhibitor, liproxstatin-1, to the combination therapy significantly abrogated the in vivo synergism between SBRT and KRAS inhibition, suggesting that treatment-induced ferroptosis at least partially drives the synergistic efficacy of this combination strategy. Our study indicates that this SBRT-KRASi combination has the potential to overcome treatment resistance and improve outcomes in PDAC patients. These data directly support the design of a planned multi-center Phase 2 clinical trial with this combination strategy in locally advanced PDAC.

cancer biology↗

bioRxiv2026

Relationship between X chromosome mosaicism, neuroanatomy and cognitive performance in females

Females have two X chromosomes, one of which is inactivated early in development with specific regions and genes escaping inactivation. Thus, X chromosome loss putatively results in decreased dosage of X chromosome escapee and pseudoautosomal genes, impacting downstream pathways. Evidence from Turner syndrome indicates that X chromosome monosomy results in consistent neuroanatomical and cognitive phenotypes. However, it remains unclear whether mosaic karyotypes, with mixed proportions of 45X and 46XX cells, attenuate these phenotypes. We examined whether X chromosome mosaicism is predicted by neuroanatomical and cognitive features. Higher proportion of 46XX cells was significantly predicted by structural properties in somatosensory, motor, visual, and language brain areas, and by performance in visuospatial, fine-motor, and language tasks. Thus, mosaicism partially rescues phenotypes linked to full 45X monosomy and may explain the role of the X chromosome not only across heterogeneous phenotypic expression in females, but also in sex differences observed in neuropsychiatric conditions.

neuroscience↗

bioRxiv2025

Mechanisms of resistance to active state selective tri-complex RAS inhibitors

Tri-complex inhibitors (TCIs) act as molecular glues to recruit cyclophilin A (CYPA) to the active (GTP-bound or ON) conformation of RAS, which in turn prevents the activation of downstream effector proteins like RAF and PI3K. Emerging data demonstrate clinical activity, including tumor regressions, in patients with RAS driven cancers. Despite being promising therapeutic interventions, the mechanisms of resistance in patients treated with these inhibitors remain unknown. Here we studied matched baseline and post-progression specimens from patients treated with the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236). Tissue or cell-free DNA specimens were collected from 40 patients with RAS-mutant non-small cell lung, colorectal, or other cancers. Eighteen patients (45%) were found to have acquired alterations in RAS signaling intermediates, including recurrent alterations in KRAS, BRAF, RAF1, MAP2K1/2 and PIK3CA. Preclinical resistance models mirrored the alterations observed in patients. We found that secondary KRAS Y64X mutations caused resistance by disrupting an important pi-pi interaction between KRAS and the indole ring of daraxonrasib, which lowers the affinity of the daraxonrasib:CYPA binary complex for active KRAS. We also identified kinase-dead and low-activity BRAF mutations in samples with acquired resistance. This is puzzling, because TCIs are expected to prevent the interaction between RAS and BRAF, which is needed for hypoactive mutants to dimerize and signal. We now show that RAF dimers are harder to displace from active RAS, as compared to their monomeric forms. Indeed, enhanced RAF dimerization attenuated the ability of TCIs to recruit CYPA to active RAS, resulting in diminished inhibition of oncogenic signaling and tumor growth. Thus, several clinical resistance alterations converge at attenuating the formation of the RAS:daraxonrasib:CYPA tri-complex, either by preventing daraxonrasib binding or by inducing RAF dimers.

cancer biology↗

bioRxiv2025

Inhibitors of oncogenic Kras specifically prime CTLA4 blockade to transcriptionally reprogram Tregs and overcome resistance to suppress pancreas cancer

Lack of sustained response to oncogenic Kras (Kras*) inhibition in preclinical models and patients with pancreatic ductal adenocarcinoma (PDAC) emphasizes the need to identify impactful synergistic combination therapies to achieve robust clinical benefit. Kras* targeting results in an influx of T cell infiltrates including Tregs, effector CD8+ T cells and exhausted CD8+ T cells expressing several immune checkpoint molecules in PDAC. Here, we probe whether the T cell influx induced by different Kras* inhibitors enable a therapeutic window to prime adaptive immune response in PDAC. Here we report a specific synergy between KrasG12D allele specific inhibitor, MRTX1133 or multi-selective pan-RAS inhibitor, RMC-6236 and anti-CTLA4 immune checkpoint blockade. In contrast, attempted therapeutic combination with multiple other immune checkpoint inhibitors, including anti-PD1, anti-Tim3, anti-Lag3, anti-Vista and anti-4-1BB agonist antibody failed due to compensatory mechanisms mediated by other checkpoints on exhausted CD8+ T cells. Specifically, anti-CTLA4 therapy in Kras* targeted PDAC transcriptionally reprograms effector T regs to a naive phenotype, reverses CD8+ T cell exhaustion and is associated with recruitment of tertiary lymphoid structures (TLS) containing follicular B cells, interferon (IFN)- stimulated/ activated B cells, plasma cells and germinal center B cells to functionally enable efficacy of immunotherapy with long-term survival. In this regard, inhibition of the TLS with lymphotoxin-{beta} inhibitor (LTBi) or direct B cell depletion reversed the survival benefit conferred by the combination therapy and highlights the function of TLS in generating productive anti-tumor immune responses. Further, single cell ATAC sequencing analysis revealed that transcriptional reprogramming of Tregs is epigenetically regulated by downregulation of AP-1 family of transcription factors including Fos, Fos-b, Jun-b, Jun-d in the IL-35 promoter region. This study reveals an actionable vulnerability in the adaptive immune response in Kras* targeted PDAC with relevant clinical implications.

cancer biology↗