Biology subjects

Nonaka, K.

Publications and source records attributed to Nonaka, K..

4 recordsLinked to original sources

bioRxiv2026

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

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.

Cancer Biology↗

bioRxiv2026

Temporal regulation of G2 phase avoids therapy-induced senescence caused by DNA replication stress-inducing drugs and provides synergistic cytotoxicity

The cellular response to DNA replication stress (DRS) provoked by anticancer drugs involves activation of the G2/M checkpoint (which promotes transient cell cycle arrest at G2 phase) and DNA repair, followed by induction of apoptosis or senescence. Here, we activated the p53-p21 pathway and ATR using DRS-inducing drugs, and found that that the transition to senescence depends on the duration of the G2 phase. Shortening of G2 duration by G2/M checkpoint inhibitors led not only to a switch in cell fate from senescence to mitotic entry, but also to effective cell death through carry-over of chromosomal aberrations (generated by DRS-inducing drugs) into mitosis and subsequent mitotic progression. Such enhanced cell death was also observed in p53 deficient cells, which do not normally undergo senescence. Thus, we propose that temporal regulation of G2 phase is an approach to enhancing the effects of DRS-inducing drugs in a manner that is independent of p53 status.

cell biology↗

bioRxiv2025

Estimating fruit tree growth curves in breeding field using fragmented longitudinal data: An application to citrus hybrid seedlings

Vegetative and reproductive growth in fruit trees is interconnected, and analyzing this relationship can provide valuable insights into fruit quality. However, characterizing vegetative growth through growth models is challenging because of the difficulty in obtaining longitudinal data, given the slow growth rate. In breeding fields, in contrast, seedlings of different ages are planted, allowing for simultaneous measurements that yield a dataset resembling longitudinal data with missing values --termed "fragmented longitudinal data." Because longitudinal data are obtained from a single measurement, they can potentially shorten the period required for growth curve estimation. Bayesian nonlinear models offer advantages in estimating curves from incomplete data. In this study, we generated fragmented longitudinal data using genome data with 45,929 markers from 624 citrus hybrid seedlings and applied a Bayesian nonlinear model to explore its potential. We also incorporated genomic information into the model to assess the impact of the estimation accuracy. Our simulations indicated that the Bayesian nonlinear models ability to interpolate missing values significantly improved the estimation performance. At best, the mean square error of the parameter characterizing the later growth stage was reduced by 84.3 mm2. Although the improvement from incorporating genomic information was modest, it still surpassed models that lacked genomic data. We also predicted the curves of untested individuals using the estimated parameters. Although the prediction accuracy of each parameter measured by the correlation coefficient was lower than 0.5, one parameter consistently showed a better accuracy. Further research is required to reveal the advantages of integrating genomic data for better predictions.

genetics↗

bioRxiv2023

The anti-tumor effect of trifluridine via induction of aberrant mitosis is unaffected by mutations modulating p53 activity

The fluorinated thymidine analogue trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage repair responses during G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense-mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of p53 function.

cell biology↗