USP20-mediated PGAM1 stabilization promotes glycolysis and confers osimertinib resistance in non-small cell lung carcinoma

LINC00511 drives osimertinib resistance in LUAD via PERK kinase: A clinical biomarker with enzymatic therapeutic potential.

BACKGROUND Osimertinib resistance is a major challenge in the treatment of EGFR-mutated lung adenocarcinoma (LUAD), and the role of LINC00511 in this process remains unclear. METHODS We analyzed LINC00511 expression, patient prognosis, and its correlation with EIF2AK3 (encoding PERK) in LUAD using the GEPIA2 database, and further validated its circulating levels in patient peripheral blood by RT-qPCR. In vitro experiments, we constructed osimertinib-resistant H1650-OS and H1975-OS cell lines and regulated the expression of LINC00511 using genetic means. We evaluated the effects on resistance through functional experiments and used Western blot to detect PERK/Nrf2 and ER stress (ERS)-related proteins. Finally, we established a xenograft model to validate the in vitro findings in vivo. RESULTS The results showed that elevated LINC00511 levels in patients with osimertinib resistance, and positively correlated with PERK. Knockdown of LINC00511 could block the activation of the PERK/Nrf2 axis, inducing ERS. In vivo experiments confirmed that silencing LINC00511 enhances the inhibitory effect of osimertinib on osimertinib-resistant LUAD. Mechanistically, LINC00511 inhibits ERS through the PERK-Nrf2 pathway, thereby driving resistance. CONCLUSION These findings provide clinical evidence for the early diagnosis and risk stratification of Osimertinib resistance, and suggest that targeting the LINC00511-PERK-Nrf2 axis may become a novel therapeutic strategy for restoring drug sensitivity, offering potential targets for the development of intelligent diagnostic and therapeutic nanomaterials.

AARS1-catalyzed H4K12 lactylation promotes HCC resistance to targeted therapy by activating RAPGEF3-RAP1 signaling.

A novel metabolic-epigenetic mechanism whereby lactate modulates hepatocellular carcinoma sensitivity to targeted therapies through histone lactylation is delineated and suggests AARS1-H4K12la-RAPGEF3 axis may serve as an interventional target to overcome targeted drug resistance, offering a promising strategy to enhance clinical outcomes in HCC patients.

USP15-mediated deubiquitination of FIS1 impairs mitochondrial function and sensitizes bladder cancer cells to radiotherapy

Targeting EP2 overcomes osimertinib-tolerant persisters through metabolic and inflammatory reprogramming in non-small cell lung cancer.

Although osimertinib is an effective third-generation EGFR inhibitor for EGFR-mutant NSCLC, the emergence of acquired resistance continues to limit its long-term clinical benefit. However, the early cellular adaptations that allow residual tumor cells to survive osimertinib exposure are not fully understood. Here, we combined patient-derived NSCLC samples, transcriptomic analyses, cellular experiments, and xenograft models to determine whether prostaglandin E2 receptor subtype 2 (EP2) contributes to osimertinib-tolerant persister (OTP) cells. EP2 was markedly upregulated in OTP NSCLC cells and patient-derived tumor tissues. Mechanistically, EP2 activation induced Ser641 site-specific phosphorylation of glycogen synthase (GYS1), which in turn led to aberrant glycogen accumulation, suppressed glycolytic metabolism, and elevated intracellular succinate levels. The accumulated succinate stabilized hypoxia-inducible factor-1α (HIF-1α), thereby driving the transcription of proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). This metabolic-inflammatory feedback loop enhanced cancer cell survival and facilitated the development of OTPs. Additionally, genetic or pharmacologic inhibition of EP2 effectively reversed these pathogenic alterations, restored osimertinib sensitivity in OTP cells, and attenuated tumor growth in xenograft models. Clinically, high expression levels of EP2, phosphorylated GYS1, and HIF-1α in tumor tissues correlated with poor therapeutic response to osimertinib, and elevated serum concentrations of inflammatory cytokines in NSCLC patients. Collectively, EP2 serves as a critical regulator linking metabolic reprogramming and inflammatory signaling to OTPs. These findings suggest that EP2 blockade may serve as a rational combination strategy for limiting early adaptive resistance and improving responses to EGFR-TKIs in EGFR-mutant NSCLC.

Targeting PGAM1 Y119 Phosphorylation Resensitizes Non-Small Cell Lung Cancer to Cisplatin Therapy by Promoting Oxidative Stress and DNA Damage.

Cisplatin resistance remains a primary challenge in the clinical management of non-small cell lung cancer (NSCLC), yet the regulatory targets underlying this resistance remain largely unknown. It is well established that cisplatin kills tumor cells through the induction of DNA damage and the accumulation of reactive oxygen species (ROS), which exacerbate DNA damage. Here, we identify the glycolytic metabolic enzyme PGAM1, and specifically its elevated activity in cisplatin-resistant tumors, as a pivotal metabolic driver of this resistance. Y119 phosphorylation, which reflects increased PGAM1 activity, is significantly elevated in NSCLC patient tissues and further amplified in cisplatin-resistant cell lines. Mutation of the PGAM1 Y119 phosphorylation site (Y119F) resensitizes resistant cells to cisplatin both in vitro and in vivo. Mechanistically, Y119-phosphorylated PGAM1 enhances flux through the pentose phosphate pathway (PPP) and the serine synthesis pathway (SSP). This metabolic reprogramming promotes nucleotide biosynthesis and NADPH generation, thereby alleviating cisplatin-induced DNA damage and oxidative stress. In vivo, a PGAM1-derived pY119-mimetic cell-permeable peptide (Y119E-TAT) that competitively disrupts PGAM1 binding to its histidine kinase, thereby inhibiting PGAM1 activity, potently inhibits cisplatin-resistant NSCLC tumor growth. Together, these findings reveal a novel mechanism by which PGAM1 Y119 phosphorylation drives chemoresistance and suggest that targeting this phosphorylation event represents a potential therapeutic strategy to overcome cisplatin resistance in NSCLC.

Abstract A062: Selective USP10 inhibition by GL-458 re-sensitizes platinum-resistant non-small cell lung cancer through DNA damage response disruption

Platinum-based chemotherapy remains one of the standard treatments for advanced non-small cell lung cancer (NSCLC); however, most patients eventually relapse because of acquired resistance. A major driver of therapeutic resistance is hyperactivation of the DNA damage response (DDR), which allows tumor cells to repair chemotherapy-induced DNA lesions and evade cytotoxic stress. The deubiquitinating enzyme USP10 stabilizes multiple DDR and pro-survival proteins, making it an attractive therapeutic target for re-sensitizing resistant tumors. Inhibition of USP10 may impair DNA repair signaling and enhance anti-tumor activity in resistant NSCLC models. We developed selective and potent USP10 inhibitors through medicinal chemistry optimization. GL-458 was identified as the lead USP10 inhibitor and demonstrated improved selectivity in deubiquitinase (DUB) assays compared with previously reported USP10 inhibitors, including Wu-5 and P22077. P22077 functions as a covalent, non-specific inhibitor, whereas Wu-5 is a non-covalent, non-selective inhibitor. In cellular viability MTT assays, GL-458 demonstrated greater potency, with approximately 3-fold lower IC50 values than Wu-5 and approximately 1.7-fold lower IC50 values than P22077. GL-458 target selectivity and target-dependent cytotoxicity were further evaluated using mouse KRAS/TP53-driven (KP) and USP10-knockout KPU NSCLC models. MTT and colony formation assays demonstrated robust, dose-dependent suppression of proliferation and clonogenic survival. Combination treatment studies using CellTiter-Glo showed that GL-458 effectively re-sensitized cisplatin-resistant cells. Flow cytometric analysis using the Click-iT EdU assay demonstrated early G0/G1 cell-cycle arrest accompanied by ATM/ATR activation, increased gamma-H2AX, and elevated cleaved PARP-1 expression. Immunofluorescence analyses revealed accumulation of gamma-H2AX, 53BP1, and Chk1 foci, consistent with impaired DNA repair capacity. Co-treatment with ATM inhibitors further validated the involvement of DDR signaling in mediating the anti-tumor effects of USP10 inhibition. Generative AI tools were used solely for language editing and improvement of abstract clarity; all scientific content, data interpretation, and conclusions were generated and verified by the authors. Sadaf Dorandish, Komal Bhayekar, Amirreza Samarbakhsh, Babita Kushwaha. Dorandish, Yubin Ge, Navnath S Gavande. Selective USP10 inhibition by GL-458 re-sensitizes platinum-resistant non-small cell lung cancer through DNA damage response disruption [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr A062.