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Article
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Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling
Resistance to glucocorticoids (GC) is a major obstacle for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Here, the authors report that GC-triggered CXCR4 internalization promotes a phospholipase C (PLC)-mediated cell survival pathway, driving GC resistance in B-ALL.
- Souleymane Abdoul-Azize
- , Rihab Hami
- & Olivier Boyer
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Article
| Open Access
H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours
Histone H2AX has a known role in DNA damage repair but interestingly, its loss is associated with resistance to poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-deficient tumours. Here, the authors identify a role of γH2AX in the degradation of replication forks and demonstrate that H2AX loss drives PARP inhibitor resistance via increased stressed fork stability in BRCA-deficient tumours.
- Diego Dibitetto
- , Martin Liptay
- & Sven Rottenberg
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Article
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Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer
The ability of anti-cancer therapies such as radiotherapy, chemotherapy and immunotherapy to induce ferroptosis has been linked to their efficacy. Here, the authors demonstrate that SOX13 promotes ferroptosis-resistance via transactivation of SCAF1, identifying SOX13 as a targeted therapeutic vulnerability in gastric cancer.
- Hui Yang
- , Qingqing Li
- & Mingzhe Ma
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Article
| Open Access
Ferritinophagy mediates adaptive resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer
The mechanisms leading to acquired resistance to targeted therapy in cancer are not completely understood. Here, the authors show that ferritinophagy mediates adaptive resistance to Osimertinib, and that combining this EGFR tyrosine kinase inhibitor with copper ionophores improves its therapeutic efficacy in preclinical models of non-small cell lung cancer.
- Hui Wang
- , Qianfan Hu
- & Feng Jiang
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Article
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Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer
Remaining drug-tolerant persistent (DTP) cancer cells limit the efficacy of targeted therapy in EGFR, ALK and KRAS mutant non-small cell lung cancer (NSCLC). Here, the authors show that focal adhesion kinase (FAK)-YAP signalling supports DTP cells promoting residual disease and targeting this pathway improved tumour response in NSCLC preclinical models.
- Franziska Haderk
- , Yu-Ting Chou
- & Trever G. Bivona
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Article
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Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
The effect of noncoding genetic variation on acute lymphoblastic leukemia treatment response is not fully understood. Here, the authors functionally evaluated variants associated with pharmacological traits and validate the role of rs1247117 in gene regulation impacting therapeutic response.
- Kashi Raj Bhattarai
- , Robert J. Mobley
- & Daniel Savic
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Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma
Targeting oncogenic ALK activity in neuroblastoma is an attractive therapeutic strategy but success has been limited by resistance to ALK inhibitors. Here, the authors identify loss of miR-1304-5p as a driver of ALK inhibitor resistance via regulation of NRAS, and therapeutically target this axis with the addition of a farnesyltransferase inhibitor in preclinical models of neuroblastoma.
- Perla Pucci
- , Liam C. Lee
- & Suzanne D. Turner
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Article
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Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer
Ferroptosis plays an important role in response to radiotherapy and chemotherapy, however, the sensitivity of cancer cell to ferroptosis varies. Here, the authors show that ODC1-mediated polyamine synthesis induces ferroptosis and demonstrate the potential of targeting this axis by combining polyamine supplements with radiotherapy or chemotherapy in preclinical lung cancer models.
- Guoshu Bi
- , Jiaqi Liang
- & Cheng Zhan
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Article
| Open Access
PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer
CDK4/6 inhibitors have improved outcomes for patients with ER+ breast cancer, however, those with loss of RB1 function often fail to respond. Here, the authors identify a vulnerability of ER + /RB1- breast cancer on PRMT5 and via dual blockade of ER and PRMT5 therapeutically target this in patient-derived xenograft models.
- Chang-Ching Lin
- , Tsung-Cheng Chang
- & Carlos L. Arteaga
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Article
| Open Access
MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation
Several molecular mechanisms, including retinoblastoma protein RB1 deficiency, explain CDK4/6 inhibitors resistance in cancer. Here, the authors show that MYC amplification induces CDK4/6 inhibitors resistance through transcriptional regulation of KLHL42, leading to RB1 degradation and targeting MYC overcomes CDK4/6 resistance in preclinical cancer models.
- Jian Ma
- , Lei Li
- & Lei Li
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Article
| Open Access
Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma
Acquired resistance to immune checkpoint inhibitors represents an important clinical challenge. Here, in a pancreatic ductal adenocarcinoma model of acquired resistance to immunotherapy, the authors show that plasticity-induced repression of Irf6 is associated with tumor cell-intrinsic resistance to cytotoxic T-cell activity.
- Il-Kyu Kim
- , Mark S. Diamond
- & Ben Z. Stanger
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Article
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Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma
The anti-CD38 monoclonal antibody Daratumumab is approved for the treatment of multiple myeloma but efficiency is curtailed by secondary resistance. Here authors show that the antibody-dependent cellular cytotoxicity, which is the main mechanism of action for Daratumumab, is regulated by KDM6A via Histone H3 K27 methylation of CD38 and CD48, downregulation of which leads to drug resistance.
- Jiye Liu
- , Lijie Xing
- & Kenneth C. Anderson
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Article
| Open Access
The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma
The application of fibroblast growth factor receptor (FGFR)−2 selective tyrosine kinase inhibitors (TKIs) in cholangiocarcinoma (CCA) with FGFR2 fusions has been reported to lead to mutations in the kinase domain of FGFR2.
Here, the authors report that non-selective TKI, lenvatinib may be an alternative in case of insurmountable side effects to specific FGFR inhibitors or to overcome and delay the development of resistance mediating FGFR2 mutations.
- Stephan Spahn
- , Fabian Kleinhenz
- & Michael Bitzer
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Article
| Open Access
Tracing back primed resistance in cancer via sister cells
Transcriptional cell states can drive treatment resistance in cancer. Here, the authors develop ReSisTrace to predict cell states that are primed to resist ovarian cancer treatment and validate their findings using small molecule inhibitors.
- Jun Dai
- , Shuyu Zheng
- & Anna Vähärautio
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Article
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Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC
Heterogeneous response to Enzalutamide remains a critical issue in castration-resistant prostate cancer (CRPC). Here, the authors reconstruct a CRPC-specific mechanism-centric regulatory network to identify signatures of Enzalutamide response and predict patients at risk of Enzalutamide resistance.
- Sukanya Panja
- , Mihai Ioan Truica
- & Antonina Mitrofanova
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Article
| Open Access
Cell cycle arrest induces lipid droplet formation and confers ferroptosis resistance
How cell cycling coordinates with cell survival and death remains unclear. Here, the authors reveal a suppressive effect of cell cycle arrest on ferroptosis and propose a ferroptosis-inducing approach to treat slow-cycling, therapy-resistant cancers.
- Hyemin Lee
- , Amber Horbath
- & Boyi Gan
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Article
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Disrupting cellular memory to overcome drug resistance
Identifying memory and state switching in single cells remains elusive. Here, the authors develop a method, scMemorySeq, by combining cell barcoding and scRNA-seq and apply it to human melanoma cells to track lineages as they switch states between a drug-susceptible state and a state primed for drug resistance.
- Guillaume Harmange
- , Raúl A. Reyes Hueros
- & Sydney M. Shaffer
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Article
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Glycerol-weighted chemical exchange saturation transfer nanoprobes allow 19F/1H dual-modality magnetic resonance imaging-guided cancer radiotherapy
Radiotherapy (RT) sensitizers have been used to overcome tumor hypoxia and improve response to RT. Here the authors design and characterize a pH and oxygen sensitive nano-molecular probe for imaging-guided cancer radiotherapy.
- Rong A
- , Haoyu Wang
- & Xilin Sun
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Article
| Open Access
USP36 stabilizes nucleolar Snail1 to promote ribosome biogenesis and cancer cell survival upon ribotoxic stress
Targeting ribosome biogenesis with the ribosome inhibitor, homoharringtonine (HHT), is effective in leukaemia but not in solid tumours. Here, the authors demonstrate that in solid tumours, activation of JNK signaling following HHT-induced ribosomal stress promotes Snail1 accumulation in the nucleolus which facilitates ribosome biogenesis and resistance to HHT.
- Kewei Qin
- , Shuhan Yu
- & Yong Yi
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Article
| Open Access
URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers
Despite being a promising treatment for hepatocellular carcinoma (HCC), resistance to tyrosine kinase inhibitors (TKI) present a major obstacle. Here, the authors demonstrate that lipid metabolism reprogramming via URI mediated stearoyl-CoA desaturase 1 upregulation present a targetable driver of sorafenib resistance in HCC.
- Zhiwen Ding
- , Yufei Pan
- & Lu Wang
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Article
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Interferon restores replication fork stability and cell viability in BRCA-defective cells via ISG15
Here the authors show that the basal activation of the interferon/ISG15 pathway is required for the stability of nascent DNA during replication and its upregulation promotes viability, proliferation and acquisition of drug resistance in BRCA1/2 deficient cells.
- Ramona N. Moro
- , Uddipta Biswas
- & Lorenza Penengo
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| Open Access
PARP14 inhibition restores PD-1 immune checkpoint inhibitor response following IFNγ-driven acquired resistance in preclinical cancer models
IFNγ signalling has been described as a potential driver of resistance to immune checkpoint blockade (ICB) therapy. Here the authors report that PARP14 is upregulated in chronic IFNγ-treated cancer cell models and that its inhibition restores response to anti-PD-1 therapy in preclinical cancer models.
- Chun Wai Wong
- , Christos Evangelou
- & Adam F. L. Hurlstone
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Article
| Open Access
Hypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas
The metabolism of temozolomide (TMZ) to form methyldiazonium ions and 5-aminoimidazole-4-carboxamide (AICA) results in DNA damage, despite this, resistance frequently occurs in glioblastoma. Here, the authors demonstrate that AICA is further metabolised by HPRT1 into AICAR, which activates AMPK signalling and increases DNA damage repair. Targeting this axis in preclinical glioblastoma models sensitised tumours to TMZ.
- Jianxing Yin
- , Xiefeng Wang
- & Xu Qian
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Article
| Open Access
ABCC1 and glutathione metabolism limit the efficacy of BCL-2 inhibitors in acute myeloid leukemia
BCL-2 inhibition using Venetoclax has emerged as a promising therapy in Acute Myeloid Leukaemia (AML), but primary and acquired resistance is a main limitation of this treatment. Here, the authors show that the ABC transporter ABCC1 (MRP1) together with glutathione, are associated with Venetoclax resistance and represent potential targets to sensitize AML cells to BCL-2 inhibition.
- Jessica Ebner
- , Johannes Schmoellerl
- & Florian Grebien
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Article
| Open Access
AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
An effective response to chemotherapy is often associated with the promotion of type-I interferons and anti-tumor immune responses. Here the authors show that tryptophan metabolites induced by chemo-drugs interfere with STING activation and IFN-I production in bladder cancer, reducing the efficacy of chemotherapy.
- Zikun Ma
- , Zhiyong Li
- & Xiaoyu Liang
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Article
| Open Access
Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
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Article
| Open Access
A phase 1 study of nivolumab in combination with interferon-gamma for patients with advanced solid tumors
The majority of cancer patients do not respond to single agent immune checkpoint blockade and several combinatorial approaches have now been tested. Here the authors report the results of a phase I dose escalation trial of nivolumab (anti-PD1) in combination with IFN-γ in patients with advanced solid tumors.
- Matthew Zibelman
- , Alexander W. MacFarlane IV
- & Elizabeth R. Plimack
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Article
| Open Access
The RNA-binding protein LRPPRC promotes resistance to CDK4/6 inhibition in lung cancer
CDK4/6 inhibition is a promising therapeutic approach to treat cancer, but it is challenged by resistance development. Here, the authors show that the RNA binding protein LRPPRC forms a positive feedback loop with CDK6 and inhibiting LRPPRC with the FDA-approved gossypol acetate overcomes CDK4/6 inhibition resistance.
- Wei Zhou
- , Wenxi Wang
- & Xiaohong Fang
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Article
| Open Access
NOTCH4ΔL12_16 sensitizes lung adenocarcinomas to EGFR-TKIs through transcriptional down-regulation of HES1
Patients with lung adenocarcinoma (LUAD) patients carrying EGFR mutations are often treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), but sensitivity to the therapy varies. Here, using 3D printed patient derived xenograft models, the authors identify a NOTCH mutation as an indicator of favourable response to EGFR-TKI in LUAD.
- Bin Zhang
- , Shaowei Dong
- & Chang Zou
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Article
| Open Access
Increased renal elimination of endogenous and synthetic pyrimidine nucleosides in concentrative nucleoside transporter 1 deficient mice
Concentrative nucleoside transporters (CNTs) are cellular nucleoside influx systems, but their in vivo roles are poorly defined. By generating CNT1 knockout (KO) mice, here the authors show a role of CNT1 in the renal reabsorption of endogenous and synthetic nucleosides.
- Avinash K. Persaud
- , Matthew C. Bernier
- & Rajgopal Govindarajan
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Article
| Open Access
Lysyl oxidase-like 3 restrains mitochondrial ferroptosis to promote liver cancer chemoresistance by stabilizing dihydroorotate dehydrogenase
Novel strategies are needed to overcome chemotherapy resistance. Here the authors report chemotherapy induces the phosphorylation of Lysyl oxidase-like 3, which in turn stabilizes dihydroorotate dehydrogenase (DHODH) and that DHODH inhibitor sensitizes tumor cells to oxaliplatin treatment by inducing ferroptosis in liver cancer.
- Meixiao Zhan
- , Yufeng Ding
- & Xiongjun Wang
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Article
| Open Access
Dasatinib overcomes glucocorticoid resistance in B-cell acute lymphoblastic leukemia
Despite playing a central role the treatment of B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), resistance to glucocorticoids remains a major obstacle. Here, the authors identify activation of PI3K/mTOR and CREB pathways as a driver of GC-resistance in BCP-ALL and restore sensitivity using the multi kinase inhibitor, dasatinib.
- Jolanda Sarno
- , Pablo Domizi
- & Kara L. Davis
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Article
| Open Access
TRPV1 inhibition overcomes cisplatin resistance by blocking autophagy-mediated hyperactivation of EGFR signaling pathway
The emergence of cisplatin resistance and side-effects are important factors in cancer treatment failure. Here, the authors identify autophagy-mediated EGFR hyperactivation by TRPV1 promotion as a mechanism of cisplatin resistance and demonstrate the efficacy of a TRPV1 inhibitor to sensitize lung cancer to cisplatin.
- Se Jin Oh
- , Ji Yeon Lim
- & Tae Woo Kim
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Article
| Open Access
Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death
Metabolic rewiring is involved in acute myeloid leukaemia (AML) maintenance. Here the authors show that the inhibition of mannose-6-phosphate isomerase in the mannose metabolism pathway sensitizes AML to FLT3-tyrosine kinase inhibitor and standard chemotherapy via enhancing lipid peroxidation and ferroptotic cell death.
- Keith Woodley
- , Laura S. Dillingh
- & Paolo Gallipoli
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Article
| Open Access
Targeting C/EBPα overcomes primary resistance and improves the efficacy of FLT3 inhibitors in acute myeloid leukaemia
Resistance of FLT3-ITD acute myeloid leukaemia (AML) patients to FLT3 inhibitors (FLT3i) remains an urgent clinical challenge. Here, the authors identify C/EBPα activation as a mechanism of FLT3i resistance and therapeutically target C/EBPα activation in combination with FLT3i in preclinical models FLT3-ITD AML.
- Hanlin Wang
- , Guanghao Luo
- & Jia Li
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Article
| Open Access
Evolutionary route of nasopharyngeal carcinoma metastasis and its clinical significance
It is critical to understand the factors that are associated with nasopharyngeal carcinoma (NPC) progression, metastasis and response to therapy. Here, the authors analyse primary and metastatic NPC samples using bulk and single-cell sequencing, and find two distinct evolutionary routes that lead to metastasis.
- Mei Lin
- , Xiao-Long Zhang
- & Ming-Yuan Chen
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Article
| Open Access
Mapping lesion-specific response and progression dynamics and inter-organ variability in metastatic colorectal cancer
Understanding the heterogeneity of growth, response to therapy and progression dynamics in metastatic colorectal cancer (mCRC) remains critical. Here, the authors analyse lesion-specific response heterogeneity in 4,308 mCRC patients and find that organ-level progression sequence is associated with long-term survival.
- Jiawei Zhou
- , Amber Cipriani
- & Yanguang Cao
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Article
| Open Access
Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A
Phosphoproteomics is a promising tool for identifying biomarkers of treatment response in cancer. Here, the authors analyse proteomics profiling of HER2-negative female breast cancer patients and identify potential predictors of paclitaxel response.
- S. Mouron
- , M. J. Bueno
- & M. Quintela-Fandino
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Article
| Open Access
Genetic features and therapeutic relevance of emergent circulating tumor DNA alterations in refractory non-colorectal gastrointestinal cancers
Acquired resistance can be associated with genetic changes, however, clinical molecular profiling is usually only considered at the time of diagnosis. Here, the authors use serial ctDNA profiling of 449 gastrointestinal cancers to demonstrate widespread tumour evolution associated with treatment resistance and its potential implications for treatment.
- David Hsiehchen
- , Leslie Bucheit
- & Hao Zhu
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Article
| Open Access
Long noncoding RNA DIO3OS induces glycolytic-dominant metabolic reprogramming to promote aromatase inhibitor resistance in breast cancer
While aromatase inhibitors (AI) are an effective treatment for patients with estrogen receptor positive breast cancer, resistance presents a major obstacle. Here, the authors identify DIO3OS, a long noncoding RNA, as a driver of AI-resistance in breast cancer through the enhancement of aerobic glycolysis.
- Xueman Chen
- , Rong Luo
- & Erwei Song
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Article
| Open Access
mTOR inhibition attenuates chemosensitivity through the induction of chemotherapy resistant persisters
Chemotherapy resistance poses a major obstacle in cancer therapy. Here, the authors identify the mTOR pathway as a determinant of chemosensitivity and demonstrate that inhibition of mTOR promotes the persistence of a chemotherapy-resistant cancer-cell subpopulation.
- Yuanhui Liu
- , Nancy G. Azizian
- & Yulin Li
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Article
| Open Access
Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
Although small molecule tyrosine kinase inhibitors are effective in lung cancer driven by mutated EGFR, some receptor variants fail to respond. Here, the authors identify structural features of an important set of EGFR variants with reduced inhibitor sensitivity, guiding future inhibitor selection.
- Iris K. van Alderwerelt van Rosenburgh
- , David M. Lu
- & Yuko Tsutsui
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Article
| Open Access
Pharmacological blockade of TEAD–YAP reveals its therapeutic limitation in cancer cells
Previously, the small molecule inhibitor of transcriptional enhanced associate domain (TEAD) MGH-CP1 has been described in stem cells. Here, the authors demonstrate the utility of MGH-CP1 in cancer therapy and find treatment to increase Akt pathway activation via TEAD-Vgll3 activation, presenting a rationale for combination with Akt inhibition.
- Yang Sun
- , Lu Hu
- & Xu Wu
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Article
| Open Access
CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma
In patients with melanoma, increased RAS/mitogen-activated protein kinase (MAPK) pathway activity is known to drive chemotherapy resistance. Here, the authors identify CDK12 as a downstream effector of the RAS/MAPK pathway and therapeutic target which mediates chemotherapy resistance through increased expression of DNA repair associated genes.
- Thibault Houles
- , Geneviève Lavoie
- & Philippe P. Roux
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Article
| Open Access
Multi-omics characterization of autophagy-related molecular features for therapeutic targeting of autophagy
Autophagy has been typically associated with resistance to cancer therapy, and autophagy inhibitors have been explored in cancer. Here, the authors investigate autophagy signatures and their association with drug response in cancer, and find that autophagy induction can actually sensitise cancer cells to therapy.
- Mei Luo
- , Lin Ye
- & Leng Han
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Article
| Open Access
Retinoblastoma protein as an intrinsic BRD4 inhibitor modulates small molecule BET inhibitor sensitivity in cancer
Here the authors identify retinoblastoma (RB) protein as an intrinsic inhibitor of BRD4 and demonstrate that loss of RB induces BRD4 cistrome changes in the genome and enrichment of GPCR-cAMP signaling pathway, conferring resistance to small molecule BET inhibitor.
- Donglin Ding
- , Rongbin Zheng
- & Haojie Huang
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Article
| Open Access
ZIP1+ fibroblasts protect lung cancer against chemotherapy via connexin-43 mediated intercellular Zn2+ transfer
Cancer-associated fibroblasts (CAFs) have been implicated in lung cancer chemo-resistance. Here the authors show that a zinc-transporter positive CAF subset is enriched in lung cancer models after chemotherapy and actively transfers zinc to cancer cells, promoting ABCB1-mediated chemo-resistance.
- Chen Ni
- , Xiaohan Lou
- & Zhihai Qin
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Article
| Open Access
Proteomic characterization of gastric cancer response to chemotherapy and targeted therapy reveals potential therapeutic strategies
The mechanisms of resistance to therapy in gastric cancer remain to be explored. Here, proteomic profiling of 206 tumour tissues from patients treated with chemotherapy and anti-HER2-based therapy results in the identification of four molecular subtypes and the development of prognostic models.
- Yan Li
- , Chen Xu
- & Chen Ding
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Article
| Open Access
Gene expression based inference of cancer drug sensitivity
Predicting treatment response in cancer remains a highly complex task. Here, the authors develop Precily, a deep neural network framework to predict treatment response in cancer by considering gene expression, pathway activity estimates and drug features, and test this method in multiple datasets and preclinical models.
- Smriti Chawla
- , Anja Rockstroh
- & Debarka Sengupta
The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity