Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.07.10.737883

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

Wang, T.·Wang, L.·Xu, J.·Guo, Y.·Xia, L.·Li, Y.·Guan, F.·Gan, B.·Hong, D. S.·Bernard, V.·Jiang, D.·Koong, A. C.
View original source ↗Export metadata ↓

Abstract

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.

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Wang, T., Wang, L., Xu, J., Guo, Y., Xia, L., Li, Y., Guan, F., Gan, B., Hong, D. S., Bernard, V., Jiang, D., Koong, A. C.. 2026-07-13. Concurrent Stereotactic Body Radiation Therapy and KRAS Inhibition Synergistically Improve Pre-clinical Pancreatic Cancer Treatment. https://doi.org/10.64898/2026.07.10.737883

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

m6A-Driven Intratumoral Cholesterol Biosynthesis Fuels Castration-Resistant Prostate Cancer Progression

Both nuclear pore complexes (NPCs) and RNA N6-methyladenosine (m6A) machinery are indispensable for proper cellular function. Although their collaborative roles in the nuclear export of messenger RNAs (mRNAs) have been reported, it remains ambiguous whether and how this collaboration may contribute to cancer progression. Here we identify a functional cooperation between NPCs and m6A signaling that promotes the development of castration-resistant prostate cancer (CRPC). We showed that nuclear export of m6A-modified mRNAs, mediated by the interaction between RNA methyltransferase METTL3 and the nucleoporin NUP93, is functionally coupled to cholesterol biosynthesis. Given that cholesterol-fueled intratumoral androgen production is one of the mechanisms driving CRPC, we demonstrated that overexpression of the wild-type METTL3 or NUP93, but neither the enzymatically dead METTL3 nor the mutant NUP93 that loses METTL3-interacting capability, elevates intracellular levels of androgens, activates AR signaling under castrate condition, and promotes androgen-independent growth of prostate cancer cells both in vitro and in vivo. Importantly, pharmacological inhibition of METTL3 or targeted demethylation on mRNAs encoding key cholesterol biosynthesis enzymes effectively suppressed CRPC malignancy. Together, these findings uncover a therapeutically targetable m6A-METTL3-NUP93 axis that links nuclear mRNA export and metabolic reprogramming to fuel CRPC progression, providing a conceptually new strategy for the treatment of this lethal disease.

cancer biology↗
bioRxiv2026

ST6Gal2 promotes α2,6-sialylation and aggressive phenotypes in neuroblastoma cells

Neuroblastoma is the most common extracranial solid tumor of childhood. Its clinical behavior ranges from spontaneous regression to lethal, treatment-refractory disease. Aberrant 2,6-sialylation contributes to aggressive phenotypes in many cancers, but the role of ST6Gal2, a neural-enriched 2,6-sialyltransferase, in neuroblastoma is largely unexplored. Here, we examine the clinical and functional significance of ST6Gal2 in neuroblastoma. In two independent public cohorts (SEQC, n=498; Kocak, n=649), high ST6GAL2 expression was associated with significantly worse overall and event-free survival. In the SEQC cohort, ST6GAL2 expression was higher in high-risk and MYCN-amplified tumors, varied across International Neuroblastoma Staging System stages, and correlated positively with a mesenchymal transcriptional signature (Spearman {rho}=0.181). The mesenchymal correlation was reproduced in the Kocak cohort ({rho}=0.204). Stable shRNA-mediated knockdown of ST6GAL2 in SK-N-AS and SK-N-BE(2) cells reduced proliferation and viability, impaired wound closure, and decreased migration and invasion. In preliminary experiments in SK-N-AS cells, ST6GAL2 knockdown reduced binding of Sambucus nigra agglutinin, consistent with a role for ST6Gal2 in 2,6-sialylation. Together, these findings link ST6Gal2 expression to aggressive clinical and transcriptional features and pro-tumorigenic phenotypes in neuroblastoma and nominate ST6Gal2-mediated sialylation as a candidate pathway for mechanistic study.

cancer biology↗
bioRxiv2026

Unsupervised transcriptomic analysis of paired pre- and post-treatment specimens reveals divergent chemoimmunomodulatory induction trajectories in breast cancer

The immunomodulatory effects of chemotherapy (chemoimmunomodulation; CIM) are clinically consequential and heterogeneous, yet no systematic framework exists for classifying the immunomodulatory trajectory a tumor follows in response to treatment (CIM trajectory). Here, we present the CIM Induction Classifier (CIMIC), an unsupervised clustering pipeline leveraging delta gene expression across 3,189 CIM-related genes to classify specimens chemoimmunomodulatory trajectory. Applied to two pre- and post-chemotherapy breast cancer (BC) datasets (NKI/SMC, N = 36; NEO, N = 19) and nine epirubicin-perturbed triple-negative BC (TNBC) cell lines, CIMIC identified two divergent CIM trajectories: a functional CIM (Fun-CIM) trajectory, broadly conserved across tumors and cell lines and characterized by induction of inflammatory cell death, antigen presentation, viral mimicry, and adaptive immune activation programs, and a dysfunctional CIM (Dys-CIM) trajectory, characterized by induction of proteostatic and metabolic stress-adaptation programs, reduced immune cell abundances and cytotoxic activity, and enrichment of aggressive BC subtypes. Using survival and longitudinal transcriptomic data in NKI/SMC (N = 20), treatment-induced increases in Fun-CIM-associated genes and ssGSEA scores were associated with reduced recurrence, whereas Dys-CIM-associated genes and scores were associated with increased recurrence. In multivariable analyses within independent chemotherapy-treated BC cohorts (METABRIC, N = 412; SCAN-B, N = 2,462), higher baseline Fun-CIM ssGSEA scores were associated with better outcomes, whereas higher baseline Dys-CIM ssGSEA scores were associated with worse outcomes. These findings establish CIM as a dynamic, trajectory-level process and position CIMIC as a framework for defining CIM trajectories and supporting future efforts to identify predictors, mechanisms, and therapeutic strategies that maximize beneficial CIM.

cancer biology↗