bims-meract 2026-04-12 papers

bims-meract

Biomed News

on Metabolic reprogramming and anti-cancer therapy

Issue of 2026–04–12
thirteen papers selected by
Andrea Morandi, Università degli Studi di Firenze

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.
CD276 promotes CD36-mediated lipid metabolism and confers resistance to tyrosine kinase inhibitors.
Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.
DHODH-Mediated Suppression of Ferroptosis Supports Radioresistance and Represents a Therapeutic Vulnerability in Lung Cancer.
ITGB4 up-regulated by STAT3 reduces the sensitivity of bladder cancer to cisplatin by suppressing p53.
Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.
Omega-3 fatty acid DHA induces ferroptosis in colorectal cancer patient-derived organoids and drug-tolerant cells.
Neddylation inhibition sensitizes gastric cancer to 5-fluorouracil by targeting the post-translational stability of the metabolic enzyme dihydropyrimidine dehydrogenase.
Focused Ultrasound-Induced Mechanical Ablation Affects the Carbohydrate Metabolism of Residual/Peri-Focally Localized Glioblastoma Cells.
Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.
Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma.
Targeting the RNA-binding motif protein 15 suppresses prostate cancer progression and hormone therapy resistance by promoting androgen receptor degradation.
Dual targeting of SLC6A14 and autophagy/macropinocytosis enhances therapeutic efficacy in pancreatic ductal adenocarcinoma.

Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00251-X. [Epub ahead of print] 218488

Mitochondrial ACSS1 Links Acetate Metabolism to Pyrimidine Biosynthesis in Nutrient-Stressed B-Cell Lymphomas.

Johnvesly Basappa, Aaron R Goldman, Cosimo Lobello, Shengchun Wang, David Rushmore, Olga Melnikov, Neil V Sen, Vinay S Mallikarjuna, Priyanka Jain, Masoud Edalati, David S Nelson, Kathy Q Cai, Pin Lu, Reza Nejati, Hossein Borghaei, Pradeep K Gupta, Kavindra Nath, Kathryn E Wellen, Mariusz A Wasik.

  Acetate serves as an alternative carbon source in nutrient-limited tumors, yet its role in supporting nucleotide biosynthesis remains poorly understood. Here, we identify the mitochondrial enzyme ACSS1 as a key metabolic driver in mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). ACSS1 is frequently overexpressed and catalyzes the conversion of acetate to mitochondrial acetyl-CoA, sustaining oxidative metabolism and biosynthesis under nutrient stress. Genetic silencing of ACSS1 impairs mitochondrial respiration and disrupts acetate incorporation into acetyl-CoA, TCA cycle intermediates, glutamate, and aspartate, while markedly reducing 13C-acetate labeling of dihydroorotate and orotate, intermediates in de novo pyrimidine synthesis. Untargeted metabolomics reveal enrichment of pyrimidine biosynthesis pathways in ACSS1-high cells. Notably, acetate or uridine supplementation rescues the growth of ACSS1-deficient cells, confirming a functional link between acetate metabolism and nucleotide synthesis. Importantly, in vivo studies using two different MCL xenografts demonstrate that ACSS1 knockdown profoundly suppresses tumor growth, indicating that ACSS1 is required not only for metabolic adaptation of lymphoma cells in vitro but also in vivo. Collectively, our results uncover an ACSS1-dependent mitochondrial acetate-pyrimidine axis that sustains lymphoma growth and represents a previously unrecognized therapeutic vulnerability.

Keywords:  ACLY; ACSS1; ACSS2; CAD; DHODH; acetate metabolism; cancer metabolism; oncometabolite

DOI:  https://doi.org/10.1016/j.canlet.2026.218488
Cancer Lett. 2026 Apr 07. pii: S0304-3835(26)00255-7. [Epub ahead of print] 218492

CD276 promotes CD36-mediated lipid metabolism and confers resistance to tyrosine kinase inhibitors.

Xiaojuan Huang, Leina Ma, Yangyang Lu, Jinfeng Cui, Weiwei Qi, Jialin Song, Jing Guo, Shasha Wang, Jing Fang, Zhimin Lu, Wensheng Qiu.

  The efficacy of tyrosine kinase inhibitor (TKI)-based systemic therapy in advanced hepatocellular carcinoma (HCC) is often limited by drug resistance, the mechanisms of which remain incompletely understood. Here, we demonstrate that CD276, an immune checkpoint protein, promotes TKI resistance in HCC by reprogramming lipid metabolism. Upon TKI treatment, CD276 binds pSTAT3 and undergoes importin α/β-dependent nuclear translocation. In the nucleus, CD276 cooperates with STAT3 to promote CD36 transcription, thereby potentiating fatty acid uptake, lipid droplet accumulation, and mitochondrial fatty acid β-oxidation. This metabolic rewiring drives HCC proliferation and confers TKI resistance. Importantly, pharmacological inhibition of CD36 with sulfosuccinimidyl oleate sodium suppresses fatty acid uptake and tumor lipid metabolism, resensitizing resistant HCC cells to TKIs. Our findings reveal the CD276-STAT3-CD36 axis as a key regulator of lipid metabolic reprogramming in TKI resistance, providing a promising therapeutic target to overcome treatment resistance in HCC.

Keywords:  CD276; CD36; hepatocellular carcinoma; lipid metabolism; tyrosine kinase inhibitor resistance

DOI:  https://doi.org/10.1016/j.canlet.2026.218492
Mol Cancer Ther. 2026 Apr 09.

Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer.

Zachary A Schaaf, Shu Ning, Amy R Leslie, Masuda Sharifi, Richard Y Gao, James P Maine, Kristina D Leslie, Yuqiu Shen, Alan P Lombard, Wei Lou, Pui-Kai Li, Chengfei Liu, Marc Dall'Era, Allen C Gao.

Resistance to PARP inhibitors (PARPi) remains a major challenge in the treatment of advanced prostate cancer. Although metabolic rewiring has been implicated in this process, the molecular drivers and therapeutic vulnerabilities underlying this adaptation remain poorly defined. We integrated transcriptomic, functional, and clinical analyses to identify mitochondrial regulators of PARPi resistance. RNA sequencing and gene set enrichment analysis revealed robust enrichment of oxidative phosphorylation pathways in PARPi-resistant prostate cancer cells, with consistent upregulation of NDUFS4, a nuclear-encoded subunit of electron transport chain complex I. Elevated NDUFS4 expression correlated with poor survival in patient cohorts from TCGA and SU2C/PCF. Functional analyses demonstrated that genetic knockdown of NDUFS4 impaired complex I activity, reduced mitochondrial mass, and re-sensitized resistant cells to olaparib. Pharmacologic targeting of NDUFS4 using the niclosamide analog ARVib-7 phenocopied genetic depletion, suppressing mitochondrial respiration and enhancing olaparib efficacy to inhibit the growth of resistant spheroids. Both NDUFS4 silencing and ARVib-7 treatment induced ferroptotic stress, as evidenced by intracellular iron accumulation and altered expression of ferroptosis-associated markers including COX2, CHAC1, NRF2, and GPX4. These findings identify NDUFS4 as a key mediator of PARPi resistance and a therapeutic vulnerability in advanced prostate cancer. Targeting NDUFS4 disrupts oxidative phosphorylation and induces ferroptosis, providing a strong rationale for combination strategies with PARP inhibitors to overcome drug resistance.

DOI: https://doi.org/10.1158/1535-7163.MCT-25-1157
Cancer Res. 2026 Apr 08.

DHODH-Mediated Suppression of Ferroptosis Supports Radioresistance and Represents a Therapeutic Vulnerability in Lung Cancer.

Chao Mao, Shengrong Wu, Girish H Rajacharya, Min Wang, Zhengze Lu, David Huo, Yuelong Yan, Xiong Chen, Guang Lei, Zhihao Xu, Qidong Li, Mingchuang Sun, Xi Zhao, Li Zhuang, Dadi Jiang, Steven H Lin, Albert C Koong, Pankaj K Singh, Boyi Gan.

Radiotherapy (RT) is a mainstay in the treatment of solid tumors, including lung cancer, yet the long-term efficacy is often limited by radioresistance. RT promotes multiple different cell death processes, and gaining mechanistic insights into how metabolic cell death pathways like ferroptosis contribute to resistance could enable the development of effective modulators of radiation sensitivity. Here, through metabolomic and functional analyses, we identified dihydroorotate dehydrogenase (DHODH) as a critical regulator of radioresistance in lung cancer. DHODH expression was induced by radiation in a CREB-dependent manner, and both radiation exposure and acquired radioresistant states were associated with elevated DHODH activity. DHODH promoted radioresistance in part by generating ubiquinol, a mitochondrial lipid antioxidant that suppresses ferroptosis, and by supporting DNA repair through its role in de novo pyrimidine synthesis. While DHODH inhibition alone had limited therapeutic effect, its combination with IFN-γ (delivered directly or via anti-PD-1 immunotherapy) synergistically enhanced RT-induced ferroptosis and overcame radioresistance in preclinical models. These findings reveal a metabolic mechanism of radioresistance driven by DHODH-mediated ferroptosis defense and provide a rationale for combining DHODH inhibitors with RT and immunotherapy in lung cancer and potentially other solid tumors.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3728
Br J Cancer. 2026 Apr 09.

ITGB4 up-regulated by STAT3 reduces the sensitivity of bladder cancer to cisplatin by suppressing p53.

Zhuo Xing, Haozhe Xu, Pingxia Lin, Yulong Hong, Shuai Shao, Tiejun Yang, Yuan Li, Yongbao Wei.

BACKGROUND: Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer (BC). However, the development of cisplatin resistance limits its antitumor effects. While, the mechanism of cisplatin resistance remains unclear.
METHODS: Bioinformatics techniques were used to analyse genes and pathways associated with cisplatin therapy resistance. A variety of biological techniques were used to identify the role of ITGB4 in cisplatin sensitivity in BC and its potential molecular mechanism.
RESULTS: In this study, we demonstrated that ITGB4 plays a key role in regulating the sensitivity of p53 wild-type (WT) BC to cisplatin therapy. Our findings revealed that ITGB4 inhibits the activation of p53 by suppressing the phosphorylation at the p53-S15 site and promotes the degradation of p53 by facilitating the binding of MDM2 to p53, thereby reducing the sensitivity of BC to cisplatin.Additionally, we showed that ITGB4 influences the antitumor effects of MDM2 inhibitors when they are combined with cisplatin therapy. Furthermore, we found that the elevated expression of ITGB4 in cisplatin-resistant BC cells were mediated by STAT3 activation. The combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin in BC.
CONCLUSIONS: ITGB4 is a key molecule influencing cisplatin sensitivity in p53 WT BC, and the combination of STAT3 inhibitors can enhance the antitumor effect of cisplatin.

DOI: https://doi.org/10.1038/s41416-026-03364-7
Nat Metab. 2026 Apr 07.

Excess cysteine drives conjugate formation and impairs proliferation of NRF2-activated cancer cells.

Jennifer A Brain, Anna-Lena B G Vigil, Kristian Davidsen, Ayaha Itokawa, Abby C Jurasin, Hannah J Kerbyson, Maximilian Kobiesa, Madeleine L Hart, Sang Jun Yoon, Peter Bellotti, Juan Pablo Maianti, Gina M DeNicola, Lucas B Sullivan.

Cancer cells with constitutive NRF2 activation take up excess cystine beyond the cysteine demands of conventional pathways, implying unknown metabolic fates. Here, we develop an unbiased approach for the identification of cysteine metabolic fates and find that both known and previously uncharacterized cysteine-derived metabolites accumulate in NRF2-activated cancer cells. We identify many of these unknown metabolites as conjugates formed between cysteine and endogenous sugar metabolites, which can also be generated in vitro. We confirm the presence of these cysteine-derived conjugates in murine lung cancer models and primary human lung cancer samples, and their enrichment in NRF2-activated tumours in each context. Mechanistically, NRF2 promotes cystine uptake by driving SLC7A11 expression, which increases intracellular cysteine levels to promote these cysteine fates in a panel of cancer cell lines. Finally, we show that NRF2 activation creates a sensitivity to high environmental cystine, which impairs cell proliferation through excess free cysteine, and can be mitigated by sequestration into cysteine-derived conjugates. Overall, these findings reveal a cancer-associated metabolic vulnerability to excess cysteine stress, and reveal unrecognized routes of cysteine metabolism.

DOI: https://doi.org/10.1038/s42255-026-01499-8
Cell Death Dis. 2026 Apr 11.

Omega-3 fatty acid DHA induces ferroptosis in colorectal cancer patient-derived organoids and drug-tolerant cells.

Laura di Blasio, Marianela Vara-Messler, Barbara Peracino, Elena Masti, Vanesa Cepas-López, Livio Trusolino, Alberto Puliafito, Andrea Bertotti, Valentina Monica, Luca Primo.

Several epidemiological and preclinical studies suggest that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) exert anticancer activity at multiple stages of colorectal cancer (CRC) progression. However, inconsistent clinical evidence and the lack of a clearly defined molecular mechanism underlying the antitumor effects of n-3 PUFAs have raised doubts about their efficacy as anticancer therapies. To address these issues, we investigated the effects of the n-3 PUFA docosahexaenoic acid (DHA) in a collection of CRC patient-derived tumor organoids (PDTOs), a powerful platform for functional analysis of patient-specific tumors. DHA treatment markedly reduced CRC cell viability in a time- and concentration-dependent manner without inducing apoptosis. CRC-derived PDTOs exhibited pronounced sensitivity to DHA, irrespective of KRAS or TP53 mutational status, whereas organoids from normal colon tissue were less affected. Mechanistically, DHA induced ferroptosis in both CRC cells and PDTOs, as evidenced by lipid peroxide accumulation and partial rescue by ferroptosis inhibitors. Fluorescently labeled DHA localized predominantly to the endoplasmic reticulum and mitochondria, where it promoted oxidative stress. Moreover, DHA impaired the regrowth of oxaliplatin-tolerant persister cells and enhanced oxaliplatin efficacy in sequential treatment models. Together, these findings indicate that exploiting the intrinsic oxidative vulnerability of cancer cells with DHA may represent a promising, low-toxicity strategy to enhance chemotherapy efficacy and target drug-tolerant persister cells in colorectal cancer.

DOI: https://doi.org/10.1038/s41419-026-08744-8
Drug Metab Dispos. 2026 Mar 19. pii: S0090-9556(26)00043-7. [Epub ahead of print]54(4): 100274

Neddylation inhibition sensitizes gastric cancer to 5-fluorouracil by targeting the post-translational stability of the metabolic enzyme dihydropyrimidine dehydrogenase.

Qianqian Zhang, Jingyi Hu, Yangbo Liu, Dongzhao Xie, Linyue Bai, Zhuang Hu, Yanjun Tang, Siqi Feng.

  The therapeutic efficacy of 5-fluorouracil (5-FU), a cornerstone of gastric cancer chemotherapy, is predominantly limited by its catabolic inactivation in tumors. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme responsible for 5-FU inactivation, and its tumor-specific overexpression constitutes a primary mechanism of 5-FU resistance. Here, we report a novel strategy to increase the sensitivity of 5-FU by targeting the post-translational regulation of DPD. We demonstrate that the neural precursor cell expressed, developmentally downregulated 8-activating enzyme (NAE) inhibitor MLN4924 significantly enhances the antitumor activity of 5-FU in both cellular and animal models of gastric cancer without augmenting systemic toxicity. Mechanistically, MLN4924 treatment inhibits the neddylation of DPD, which is dependent on the NAE1/ubiquitin-conjugating enzyme 12 axis. This inhibition triggers the ubiquitination and subsequent proteasomal degradation of DPD, thereby reducing intracellular 5-FU catabolism and augmenting its cytotoxic effects. Our findings identify neddylation as a previously unrecognized regulatory mechanism governing DPD protein stability and activity. This work identifies the neddylation-DPD axis as a novel therapeutic target and provides a strong rationale for combining NAE inhibition with 5-FU-based chemotherapy in gastric cancer. SIGNIFICANCE STATEMENT: This study establishes neddylation as a previously unrecognized regulatory mechanism that stabilizes the drug-metabolizing enzyme dihydropyrimidine dehydrogenase to drive 5-fluorouracil resistance in gastric cancer. It further unveils that inhibiting neddylation with MLN4924 selectively depletes tumor dihydropyrimidine dehydrogenase, enhancing chemotherapy efficacy without increasing toxicity, thereby proposing a targeted strategy to overcome chemoresistance.

Keywords:  5-Fluorouracil; Dihydropyrimidine dehydrogenase; Gastric cancer; Neddylation; UBC12

DOI:  https://doi.org/10.1016/j.dmd.2026.100274
Int J Cancer. 2026 Apr 09.

Focused Ultrasound-Induced Mechanical Ablation Affects the Carbohydrate Metabolism of Residual/Peri-Focally Localized Glioblastoma Cells.

Frieda Bayler, Jonna Holler, Jacqueline Clüver, Levi Johanning, Dana Hellmold, Nils Oliver Schröder, Jessica Nojszewski, Hajrullah Ahmeti, Carolin Kubelt-Kwamin, Michael Synowitz, Janka Held-Feindt.

  Glioblastomas (GBMs) are highly aggressive and therapy-resistant brain tumors, mainly driven by stem-like cells and profound metabolic plasticity. Novel treatment strategies, including mechanical high-intensity focused ultrasound (mFUS), are being developed, but their effects on tumor metabolism remain poorly understood. To address this gap, we investigated the impact of mFUS on carbohydrate metabolism in patient-derived GBM organoids and 3D glioma stem-like cell (GSC) cultures. We showed that mFUS selectively induced the expression of glycolysis- and metabolite-transport-associated molecules (GLUT1, HK2, PKM2, LDHA, MCT1, MCT4), particularly in GSCs, as confirmed by qPCR and immunofluorescence. Functional assays demonstrated increased glucose uptake after mFUS, while lactate production remained unchanged. Notably, pharmacological inhibition of GLUT1 or MCT1 potentiated the cytotoxic effects of mFUS, significantly reducing the survival of peri-focal GSCs. Together, these results reveal that mFUS promotes metabolic adaptations in GBM cells and that combined metabolic inhibition may enhance its therapeutic efficacy.

Keywords:  carbohydrate metabolism; glioblastoma; mechanical high‐intensity focused ultrasound

DOI:  https://doi.org/10.1002/ijc.70483
Cancer Discov. 2026 Apr 08.

Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T cells in KRAS-Mutant Cholangiocarcinoma.

Jian Lin, Chen Sang, Bin Xiang, Xia Shen, Junmei Zhao, Shengshi Xu, Jiaomeng Pan, Youpei Lin, Liangqing Dong, Qianqian Chu, Guoming Shi, Jian Zhou, Jia Fan, Mao Zhang, Qiang Gao.

Metabolic reprogramming within the tumor microenvironment impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multi-omics-based metabolic subtyping in intrahepatic cholangiocarcinoma (iCCA), we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both Cyclooxygenase/Arachidonic acid (COX/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation-mediated NF-κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2 in turn enhances arachidonic acid uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2-PGE2-EP4 axis, combined with anti-PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1844
Cancer Discov. 2026 Apr 07.

Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma.

Nianxin Zhou, Fan Fei, Lin Tang, Peidong Zhang, Wei Wang, Bohao Zheng, Qiuhong Shen, Jing Yue, Liang Huang, Yiwei Du, Xiaoling Liao, Liang Ouyang, Gang Yuan, Jeremy N Rich, Shengtao Zhou, Linjie Zhao.

Despite successful immuno-oncology therapies in other cancers, they largely failed in glioblastoma(GBM). Here, natural killer (NK) cells from glioma patients show impaired oxidative phosphorylation and mitochondrial complex I activity. Multiomics profiling identified complex I subunit NDUFA9 as a critical mediator of NK cell metabolic fitness. Abundance of NDUFA9+ NK cells informed patient outcome. Ndufa9 knockout in NK cells compromised mitochondrial function, anti-tumor efficacy, and memory-like phenotype of NK cells by triggering a metabolic reprogramming toward glutamine dependence. Decreased α-ketoglutarate(α-KG)/succinate ratio in Ndufa9-deficient NK cells mediated widespread epigenetic reprogramming through inducing transcriptionally repressive histone mark H3K27me3 on key immune function genes. Resveratrol-mediated NDUFA9 activation or its overexpression enhanced NK cell anti-GBM function by restoring complex I activity. Together, these findings reveal the critical role of mitochondrial complex I activity in NK cells and highlight its potential as an actionable target to enhance NK cell-based immunotherapy for GBM patients.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0643
Mol Biomed. 2026 Apr 08. pii: 47. [Epub ahead of print]7(1):

Targeting the RNA-binding motif protein 15 suppresses prostate cancer progression and hormone therapy resistance by promoting androgen receptor degradation.

Bintao Hu, Le Li, Zhenghui Jin, Qinyu Li, Yue Wu, Jie Chen, Jihong Liu, Chenglin Han, Tao Wang.

  Androgen deprivation therapy (ADT) remains the standard treatment for advanced prostate cancer (PCa); however, most patients ultimately progress to lethal castration-resistant PCa (CRPC). Emerging evidence implicates RNA N⁶-methyladenosine (m⁶A) modification as a key regulator of cancer biology, yet its role in CRPC remains poorly understood. As a critical adaptor in the m⁶A methyltransferase complex, RNA-binding motif protein 15 (RBM15) directs m⁶A deposition to specific mRNA targets. Here, we identified RBM15 as the key methyltransferase member significantly upregulated in CRPC tissues and strongly correlated with poor patient survival. Functionally, RBM15 overexpression reduces PCa cell sensitivity to enzalutamide, whereas its knockdown suppresses tumor growth and invasion. Mechanistically, RBM15 is an androgen-responsive protein whose expression increases upon chronic androgen deprivation. It catalyzes m⁶A methylation at position A1384 of damaged DNA binding protein 1 (DDB1) mRNA, leading to YTHDF2-dependent transcript decay and reduced DDB1 protein levels. Lower DDB1 impairs K48-linked polyubiquitination of the androgen receptor (AR), thereby stabilizing AR and amplifying AR signaling. Importantly, AR transcriptionally activates RBM15, forming a feed-forward loop that drives CRPC progression. Collectively, our findings establish RBM15 as a central epitranscriptomic driver of CRPC and identify the RBM15-DDB1-AR axis as a promising therapeutic target. Dual inhibition of RBM15 and AR may offer a novel strategy to overcome treatment resistance in advanced PCa.

Keywords:  AR; DDB1; M6A; Prostate cancer; RBM15; YTHDF2

DOI:  https://doi.org/10.1186/s43556-026-00428-1
Biochem J. 2026 Apr 08. pii: BCJ20250155. [Epub ahead of print]

Dual targeting of SLC6A14 and autophagy/macropinocytosis enhances therapeutic efficacy in pancreatic ductal adenocarcinoma.

Yangzom D Bhutia, Mosharaf Mahmud Syed, Devaraja Rajasekaran, Souad R Sennoune, Tanima Sharker, Oscar Sanchez, Mary Katherine Jurek, Longfa Kou, Ruijie Chen, Vadivel Ganapathy.

  PDAC is highly desmoplastic and undergoes metabolic reprogramming to sustain their growth and proliferation. Our laboratory has identified SLC6A14, an amino acid transporter, as a novel drug target for PDAC. Genetic deletion of SLC6A14 or its pharmacological blockade with α-MLT attenuates PDAC growth by inducing amino acid deprivation. However, nutrient stress, particularly amino acid deprivation, can induce nutrient scavenging mechanisms like autophagy and macropinocytosis, thereby undermining the full anticancer potential of SLC6A14 blockade. To address this, the current work was conducted to test if SLC6A14 blockade induces autophagy and/or macropinocytosis and to further investigate if dual inhibition of SLC6A14 (α-MLT) and autophagy/macropinocytosis (HCQ) would yield a better therapeutic outcome in PDAC as opposed to targeting SLC6A14 alone. In vitro assays (MTT and colony formation) revealed that the combination treatment significantly reduced PDAC cell viability and clonogenic potential as opposed to monotherapy. Treatment model subcutaneous xenograft in athymic nude mice demonstrated a superior therapeutic outcome with the combination regimen. Collectively, our study demonstrates that the afore-described combination therapy creates a metabolic trap wherein α-MLT induces nutrient stress, while HCQ prevents autophagic and macropinocytosis compensation, thus culminating in a more potent tumor attenuation. This dual blockade represents a hitherto unexplored treatment strategy for PDAC.

Keywords:  Alpha-methyl-l-tryptophan; Macropinocytosis; Pancreatic ductal adenocarcinoma; SLC6A14; autophagy; hydroxychloroqine

DOI:  https://doi.org/10.1042/BCJ20250155