M1C IS NECESSARY FOR DARAXONRASIB RESISTANCE OF NSCLC KRAS(G12C) MUTANT CELLS

Takamori, S.; Haratake, N.; Nonaka, K.; Moriya, M.; Bhattacharya, A.; Takenaka, T.; Yoshizumi, T.; Long, M.; Kufe, D.

doi:10.64898/2026.06.20.733526

Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.06.20.733526

M1C IS NECESSARY FOR DARAXONRASIB RESISTANCE OF NSCLC KRAS(G12C) MUTANT CELLS

Takamori, S.·Haratake, N.·Nonaka, K.·Moriya, M.·Bhattacharya, A.·Takenaka, T.·Yoshizumi, T.·Long, M.·Kufe, D.

View original source ↗Export metadata ↓

Abstract

IntroductionThe RAS(ON) multi-selective daraxonrasib (RMC-6236) inhibitor is effective in patients with NSCLC KRAS mutant cancers. Tolerance to daraxonrasib invariably develops by mechanisms that remain unclear. There is no known involvement of the M1C oncogenic protein in daraxonrasib resistance. MethodsNSCLC H358 KRAS(G12C), H2122 KRAS(G12C) and patient derived MGH1112 KRAS(G12C) cells with acquired daraxonrasib resistance were investigated for M1C dependence in studies of SHP2, STAT1/3 and NF-KB activation, clonogenicity, and self-renewal capacity. ResultsWe demonstrate that M1C is induced as a protective response in NSCLC KRAS(G12C) mutant cells treated with daraxonrasib. We report that M1C forms novel cell membrane-associated biomolecular condensates with the SHP2 protein tyrosine phosphatase in driving daraxonrasib resistance. M1C integrates SHP2 activation with induction of (i) oncostatin-m/gp130/STAT3 signaling, and (ii) the NF-{kappa}B-mediated epithelial-mesenchymal transition (EMT) pathway. The functional significance of this M1C-driven pathway is supported by the demonstration that targeting STAT3 and NF-{kappa}B reverses daraxonrasib resistance. Consistent with M1C dependence, we also show that targeting M1C is effective against daraxonrasib-resistant NSCLC KRAS mutant cell line and tumor models. In contrast, M1C drives sotorasib resistance by STAT1-mediated inflammatory signaling, demonstrating that M1C confers resistance to KRAS(G12C)-selective and RAS(ON) tri-complex inhibitors by noncongruent mechanisms. ConclusionsThese findings demonstrate that M1C is required for daraxonrasib tolerance and is a potential target for the treatment of patients with NSCLC KRAS(G12C) mutant tumors refractory to this agent.

Explore related subjects

Cancer Biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Takamori, S., Haratake, N., Nonaka, K., Moriya, M., Bhattacharya, A., Takenaka, T., Yoshizumi, T., Long, M., Kufe, D.. 2026-06-23. M1C IS NECESSARY FOR DARAXONRASIB RESISTANCE OF NSCLC KRAS(G12C) MUTANT CELLS. https://doi.org/10.64898/2026.06.20.733526

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

KEEP EXPLORING

Related preprints

bioRxiv2026

Stepwise Evolution and Epistatic Interaction of Driver Mutations from Endometrial Hyperplasia to Carcinoma

To characterize early oncogenesis, pathologically identified pre-cancerous tissue can be analyzed for the presence of cancer drivers. Here, we argue that in such studies, analyses of the driver status of variants, of the association between step-specific prevalence and progression through tumorigenesis, and of driver co-occurrence and mutual exclusivity should be accompanied by estimates of inherent mutation rate of variants and presented within an evolutionary framework of selective epistasis. To illustrate this point, we examine the transition of endometrial tissue from atypical hyperplasia to carcinoma. We apply a step-specific analysis, demonstrating that the strength of selection on somatic driver mutations promoting cell division and survival differs between hyperplasia to carcinoma. We demonstrate that mutations of PTEN, which are highly prevalent in carcinomas and have been argued to exert substantial driver effects, exhibit an even larger effect of increasing cellular division and survival within developing hyperplasias. A determination of cooccurrence or mutual exclusivity may be a product of genes sharing or differing in underlying sources of mutation, as opposed to a product of biological interaction and selection. By accounting for tumor-specific mutational processes that influence co-occurrence, we calculate epistatic selective intensities between pairs of drivers. Mutations of KRAS and FGFR2 are often mutually exclusive and were indeed found to exhibit significant antagonistic selective epistasis. However, mutations of PIK3CA and PIK3R1, which also have been identified as showing mutual exclusivity, do not demonstrate significant antagonistic selective epistasis. Thus, evidence of mutually exclusivity is insufficient to determine epistasis. Accordingly, the application of quantitative approaches that distinctly analyze mutation and selection on cancer variants has the potential to substantially illuminate the trajectory of tumorigenesis and cancer progression.

Cancer Biology↗

bioRxiv2026

Comprehensive transcriptome data of melittin- and un-treated murine hepatoma Hepa 1-6 cells

Melittin, the principal bioactive peptide of bee venom, exerts potent antitumor activity against hepatocellular carcinoma (HCC). However, the comprehensive transcriptomic alterations it elicits in hepatoma cells remain poorly characterized. Here, we present an integrated transcriptome dataset from melittin- and un-treated murine Hepa 1-6 hepatoma cells, encompassing messenger RNA (mRNA) and microRNA (miRNA) expression profiles. Cells were exposed to 4 g/mL melittin in serum-free DMEM for 20 min, and total RNA was subjected to ribosomal RNA-depleted strand-specific RNA sequencing on an Illumina NovaSeq6000 platform (paired-end 150 bp) and small RNA sequencing on an Illumina HiSeq2500 platform (single-end 50 bp). Raw data were processed using Cutadapt to remove adapters and low-quality reads, yielding clean datasets with Q20 [≥] 99.85%, Q30 [≥] 98.48%, and valid data ratios exceeding 85%. All raw and processed sequencing data are publicly available. This transcriptomic resource provides a valuable resource and basis for elucidating the regulatory networks underlying melittin-induced anti-hepatoma effects. DatasetThe dataset can be accessed through the National Genomics Data Center, China National Center website by searching with the BioProject accession number PRJCA065485 Reviewers may use this link for anonymous access during the review process. Direct URL to data: Genome Sequence Archive-CNCB-NGDC. Dataset LicenseCC BY 4.0

Cancer Biology↗

bioRxiv2026

LDB1-dependent enhancer connectivity defines T-cell leukemia identities and masks metabolic vulnerabilities

Spatial enhancer connectivity is fundamental to proper gene regulation. Enhancer dysregulation has emerged as a hallmark of cancers, including T-cell acute lymphoblastic leukemias (T-ALL). T-ALL are aggressive malignancies characterized by marked transcriptional heterogeneity driven by distinct stages of developmental arrest and diverse noncoding alterations. How these cancers co-opt nuclear architecture to rewire enhancer connectivity remains poorly understood. Here, we report that the LDB1 chromatin architectural complex is an essential mediator of enhancer-oncogene looping that sustains oncogenic transcriptional programs across multiple T-ALL subtypes. Integrating bulk and single-cell transcriptomic data from patients with T-ALL and healthy hematopoietic controls, we show that the LDB1-dependent regulatory circuitry defines the molecular identities of distinct T-ALL subtypes while restricting plasticity toward alternative cell states. LDB1 loss dismantles chromatin looping among cell state-defining enhancers liberating them to form promiscuous interactions with nearby genes. This enhancer rewiring stimulates expression of key metabolic genes, creating a mevalonate pathway dependency exploitable with statin treatment. Our study establishes LDB1 as a central executor of T-ALL regulatory circuitry and more broadly illustrates chromatin rewiring as a source of targetable dependencies in cancer.

Cancer Biology↗