Jul 2026· Cancer Research· Vol 86, pp. P87-P87· 0 citations
TL;DR
C1 is presented as a novel therapeutic agent for KRAS-mutant PDAC and the concept of hyperactivating oncogenic KRAS to selectively induce ferroptotic cancer cell death is introduced.
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) has a dismal prognosis and limited treatment options. With ∼90% of PDAC cases harboring KRAS mutations, targeting KRAS has been a major therapeutic focus. However, its small size and high affinity for GTP present challenges for direct inhibition. Our lab previously identified Merodantoin (C1), a compound that paradoxically hyperactivates mutant KRAS and induces apoptosis, particularly in colon cancer. This study explores the efficacy and mechanism of C1 in KRAS-mutant PDAC. We treated PDAC cell lines and patient-derived organoids (PDOs) with C1 and assessed cell viability, ROS production, iron accumulation, and protein expression via flow cytometry and Western blotting. C1 exhibited selective cytotoxicity toward PDAC cells harboring KRAS G12C/G12D mutations, sparing wild-type KRAS cells. Mechanistically, C1 elevated both total and mitochondrial ROS and labile Fe2+ in all cells, but only induced lipid peroxidation and ferroptosis in KRAS G12-mutant cells. Ferroptosis inhibitors (ferrostatin-1, liproxstatin) and iron chelator (DFO) rescued these effects. C1 suppressed the GSH-antioxidant system selectively in mutant KRAS cells by reducing cystine uptake, GPX4 expression, and GSH levels in MIA PaCa-2 and PANC-1, but not in wild-type BxPC-3 cells. Resistance in BxPC-3 was linked to higher basal GPX4 levels. Silencing GPX4 sensitized BxPC-3 cells to C1, confirming its role in resistance. Furthermore, KRAS knockdown or inhibition (e.g., sotorasib) abrogated C1-induced ferroptosis, confirming KRAS as an upstream driver of this death pathway. These findings were validated in PDOs, with ongoing work in mouse models. Overall, this study presents C1 as a novel therapeutic agent for KRAS-mutant PDAC and introduces the concept of hyperactivating oncogenic KRAS to selectively induce ferroptotic cancer cell death.
Haiyuxin Zhu, Kartini Iskandar, Nur Syafiqah Binte Sulaiman, Benedict Joseph, Anne-sophie Armand, Franck Oury, Shazib Pervaiz. Drug-induced Hyperactivation of the oncogene KRAS induces ferroptosis in G12-mutant KRAS Pancreatic Ductal Adenocarcinoma (PDAC) [abstract]. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86(13_Suppl):Abstract nr P87.
Simple Summary Colorectal cancer (CRC) driven by the BRAFV600E (V600E) mutation represents one of the most clinically challenging subtypes of the disease, characterized by rapid progression and a striking resistance to conventional chemotherapy. Despite its poor prognosis, the molecular mechanisms have remained unclarified. In this study, we found a key role for NF-κB/Lipocalin 2 (LCN2)-signaling-pathway-induced ferroptosis in modulating cisplatin sensitivity of V600E-overexpressing CRC cells to cisplatin within a KRAS-mutant cellular background. The results show that V600E overexpression cells exhibit suppressed NF-κB/LCN2 activation and insensitivity to cisplatin treatment. The NF-κB/LCN2 signaling could induce ferroptosis through increasing the accumulation of iron, leading to activation of the Fenton reaction and increasing ROS levels. Restoring LCN2 expression in V600E overexpression cells could partially attenuate the inhibition of ferroptosis and chemoresistance of cisplatin. Interestingly, we further found an unexpected interplay between ferroptosis and apoptosis, which is also regulated by LCN2. Taken together, these findings imply LCN2 as a potential therapeutic target. Aiming the crosstalk between ferroptosis and apoptosis may offer a potential strategy to overcome chemotherapy resistance of this high-risk CRC subtype.
M. Feng, Xuesong Wu, Li Jiang et al.· Cancers· 0 citations
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive form of pancreatic cancer, with a 5-year survival rate below 10%, largely due to late diagnosis, high metastatic capacity, and resistance to standard therapies. Drug repurposing guided by polypharmacology offers a time- and cost-effective strategy to identify new treatments with reduced clinical risk. Fedratinib, a JAK2 inhibitor approved for myelofibrosis, was previously identified through our bioinformatics analysis as a compound capable of reversing KRAS-driven transcriptional programs in PDAC cells. This study investigates the therapeutic potential and underlying mechanisms of fedratinib in PDAC. Two KRAS-mutant PDAC cell lines were used for in vitro analyses. Cell viability, protein expression, and cell-cycle distribution or apoptosis were assessed using MTT assays, Western blot analysis, and flow cytometry, respectively. Cellular thermal shift assays (CETSA) were performed to evaluate drug-target engagement. In vivo efficacy was examined using a PANC-1 xenograft mouse model treated with fedratinib alone or in combination with mitomycin C. Fedratinib significantly reduced PDAC cell viability, which was associated with caspase-independent cell death, and induced a non-canonical G2/M phenotype characterized by G2/M accumulation, reduced expression of mitotic markers, and accelerated mitotic exit after release from prometaphase arrest. Kinome profiling revealed off-target inhibition of multiple mitotic kinases, which was confirmed by CETSA. Combination screening identified strong synergy between fedratinib and mitomycin C, which was validated in vitro and in vivo. Overall, these findings highlight fedratinib as a promising repurposed therapeutic agent for PDAC and support its combination with mitomycin C as a potential new treatment strategy.
Hui-Ying Li, Pei-Ming Yang· Molecular Cancer Therapeutic...· 0 citations
Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with about 50% of patients presenting with KRASG12D mutations. Small molecule inhibitors targeting KRASG12D suppress PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be elucidated. Here, integrated spatial transcriptomics, single-cell RNA sequencing, and CODEX-based spatial proteomics analyses of PDAC mouse models uncover that while KRASG12D inhibition by MRTX1133 initially increases CD11c+ cells and T cell infiltration proximal to cancer cells, long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8. CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself or in combination with αCTLA-4 immunotherapy overcomes resistance to KRASG12D inhibition. We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance. Targeting of oncogenic KRAS mutations suppresses cancer growth, however relapse arises by unclear mechanisms. This study identifies mediator complex kinase CDK8 as a driver of resistance towards KRASG12D inhibition in pancreatic ductal adenocarcinoma (PDAC), promoting stromal remodeling and immunosuppression. Priming with oncogenic KRAS inhibitors and subsequent combination treatment with checkpoint immunotherapy significantly delays or prevents resistance. Long-term inhibition of oncogenic KRAS alone induces eventual therapy resistance in PDAC mouse models. CDK8 is upregulated in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON) protein states, Daraxonrasib and Zoldonrasib, respectively. CDK8 mediates KRAS inhibition resistance via reprogramming the tumor microenvironment and deficiency in immunological memory response. CDK8 confers resistance by re-initiating suppression of FAS expression and inducing secretion of the chemokine CXCL2. Targeting CDK8 overcomes resistance to KRASG12D inhibition. While tumors resistant to oncogenic KRAS inhibition also lose the ability to respond to anti-CTLA-4 immunotherapy, CDK8 inhibition in resistant tumors re-primes PDAC to anti-CTLA-4 immunotherapy efficacy. Priming with oncogenic KRAS inhibitors and subsequent combination treatment with checkpoint immunotherapy significantly delays or prevents resistance. Long-term inhibition of oncogenic KRAS alone induces eventual therapy resistance in PDAC mouse models. CDK8 is upregulated in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON) protein states, Daraxonrasib and Zoldonrasib, respectively. CDK8 mediates KRAS inhibition resistance via reprogramming the tumor microenvironment and deficiency in immunological memory response. CDK8 confers resistance by re-initiating suppression of FAS expression and inducing secretion of the chemokine CXCL2. Targeting CDK8 overcomes resistance to KRASG12D inhibition. While tumors resistant to oncogenic KRAS inhibition also lose the ability to respond to anti-CTLA-4 immunotherapy, CDK8 inhibition in resistant tumors re-primes PDAC to anti-CTLA-4 immunotherapy efficacy. Mediator complex kinase CDK8 is a novel common vulnerability for stromal resistance towards oncogenic RAS inhibition in pancreatic cancer.
Kathleen M. McAndrews, Krishnan K. Mahadevan, Bingrui Li et al.· EMBO Journal· 1 citation
The in vitro proliferation of AKP-M4 cells, but not KRAS wild-type SNU-1079 and SSP-25 cells, was reduced by the KRAS G12D mutation inhibitor MRTX-1133, which supports the development of KRAS mutation inhibitor for CCA treatment.
J. Hung, Tsai-Hsien Hung, Chun-Nan Yeh et al.· Journal of Immunology· 0 citations
Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are aggressive malignancies frequently driven by oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations associated with metabolic reprogramming and resistance to apoptosis. In this study, we evaluated the antitumor and anti-inflammatory activity of a Lepidium latifolium L.-derived formulation (CTP) enriched in glucosinolate hydrolysis products in KRAS-mutant colorectal and pancreatic cancer models. The formulation was designed to promote the generation of the epithionitrile 1-cyano-2,3-epithiopropane (CETP) through iron-dependent myrosinase-mediated sinigrin hydrolysis. CTP induced dose-dependent cytotoxicity and morphological alterations consistent with apoptosis in KRAS-mutant cancer cell lines. Treatment significantly reduced mitochondrial membrane potential, ATP production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR), indicating severe bioenergetic impairment. In parallel, CTP downregulated the metabolic and proliferative regulators C-myc, PKM2, GLUT1, and Cyclin E1. RNA-seq analysis revealed extensive transcriptional reprogramming associated with oxidative stress, metabolic adaptation, and cell-cycle regulation. In addition, CTP significantly suppressed nitric oxide, IL-6, and IL-8 production in LPS-stimulated RAW 264.7 macrophages. These findings demonstrate that glucosinolate-derived metabolites from L. latifolium interfere with metabolic and inflammatory pathways critical for KRAS-driven tumor survival and support the therapeutic potential of Brassicaceae-derived epithionitriles as multitarget anticancer agents.
María Conde-Rioll, Aiora Cenigaonandia-Campillo, Silvia Sanz et al.· Molecules· 0 citations
ABSTRACT Aims Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with poor prognosis, and gemcitabine‐based chemotherapy remains the standard first‐line treatment. However, the rapid emergence of chemoresistance limits its efficacy. Elucidating the molecular mechanisms underlying gemcitabine resistance is critical for improving therapeutic outcomes. Approaches & Results By integrating transcriptomic profiling of gemcitabine‐resistant PDAC cells, patient‐derived xenografts (PDXs), and pretreatment clinical biopsy specimens, we identified the m6A reader IGF2BP1 as a key determinant of both intrinsic and acquired gemcitabine resistance. Mechanistically, IGF2BP1 directly binds m6A‐modified FTH1 mRNA and cooperates with G3BP1‐mediated stress granule sequestration to enhance FTH1 transcript stability under chemotherapeutic stress. The stabilized FTH1 maintains intracellular iron homeostasis, limits lipid peroxidation, and suppresses ferroptosis, thereby conferring chemoresistance. Pharmacological inhibition of IGF2BP1 with BTYNB partially disrupted this regulatory axis, restored ferroptotic susceptibility, and synergistically enhanced gemcitabine efficacy in resistant PDX models without overt toxicity. Conclusions Collectively, this study uncovers a previously unrecognized epitranscriptomic mechanism linking m6A‐dependent RNA stabilization, stress granule dynamics, and ferroptosis suppression in PDAC. By identifying IGF2BP1 as a potential biomarker of gemcitabine response and a therapeutically actionable target, these findings provide a preclinical rationale for IGF2BP1‐targeted combination strategies to overcome gemcitabine resistance in PDAC.
Ying-Qin Zhu, Yue Huang, Jing-Yuan Ye et al.· Advancement of science· 0 citations