bims-cadres 2022-10-16 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2022‒10‒16
eleven papers selected by
Rana Gbyli
Yale University

Cytokines drive prostate cancer lineage plasticity.
Persistence is key.
Glutathione peroxidase 2 overexpression promotes malignant progression and cisplatin resistance of KRAS‑mutated lung cancer cells.
HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis.
ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress.
Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism.
Editorial: Ferroptosis as new therapeutic targets in cancer: From molecular mechanisms to therapeutic opportunities.
A STING operation to expose KRAS and STK11 co-mutated lung cancers.
Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres.
AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors.
Targeting androgen receptor phase separation to overcome antiandrogen resistance.

Immunity. 2022 Oct 11. pii: S1074-7613(22)00505-2. [Epub ahead of print]55(10): 1761-1763

Cytokines drive prostate cancer lineage plasticity.

Jie Li, Brian Ruffell.

Lineage plasticity is a critical mechanism of therapeutic resistance in cancer. In a recent issue of Science, Chan and colleagues demonstrate that early lineage plasticity in prostate cancer is driven by JAK-STAT inflammatory cytokine signaling.

DOI: https://doi.org/10.1016/j.immuni.2022.09.011
Nat Rev Cancer. 2022 Oct 10.

Persistence is key.

Gabrielle Brewer.

DOI: https://doi.org/10.1038/s41568-022-00525-7
Oncol Rep. 2022 Dec;pii: 207. [Epub ahead of print]48(6):

Glutathione peroxidase 2 overexpression promotes malignant progression and cisplatin resistance of KRAS‑mutated lung cancer cells.

Mei Wang, Xu Chen, Guang Fu, Mingjian Ge.

  Kirsten rat sarcoma viral oncogene homolog (KRAS) aberrations frequently occur in patients with lung cancer. Oncogenic KRAS is characterized by excessive reactive oxygen species (ROS) accumulation, thus, ROS detoxification may contribute to KRAS‑driven lung tumorigenesis. In the present study, the influence of glutathione peroxidase 2 (GPX2) on malignant progression and cisplatin resistance of KRAS‑driven lung cancer was explored. The RNA sequencing data from TCGA lung cancer samples and GEO database were downloaded and analyzed. The effects of GPX2 on KRAS‑driven lung tumorigenesis were evaluated by western blotting, cell viability assay, soft agar assay, Transwell assay, tumor xenograft model, flow cytometry, BrdU incorporation assay, transcriptome RNA sequencing, luciferase reporter assay and RNA immunoprecipitation. In the present study, GPX2 was upregulated in patients with non‑small cell lung carcinoma (NSCLC), and positively correlated with poor overall survival. Ectopic GPX2 expression facilitated malignant progression of KRASG12C‑transformed BEAS‑2B cells. Moreover, GPX2 overexpression promoted growth, migration, invasion, tumor xenograft growth and cisplatin resistance of KRAS‑mutated NSCLC cells, while GPX2 knockdown exhibited the opposite effects. GPX2 overexpression reduced ROS accumulation and increased matrix metalloproteinase‑1 (MMP1) expression in KRAS‑mutated NSCLC cells. In addition, GPX2 was directly targeted by miR‑325‑3p, while MMP1 knockdown or miR‑325‑3p overexpression partially abrogated the effects of GPX2 in NSCLC cells. In conclusion, the results indicated that GPX2 facilitated malignant progression and cisplatin resistance of KRAS‑driven lung cancer, and inhibition of GPX2 may be a feasible strategy for lung cancer treatment, particularly in patients with active KRAS mutations.

Keywords:  Kirsten rat sarcoma viral oncogene homolog; cisplatin resistance; glutathione peroxidase 2; non‑small cell lung carcinoma; reactive oxygen species

DOI:  https://doi.org/10.3892/or.2022.8422
Cell Death Dis. 2022 Oct 08. 13(10): 861

HIF-α activation by the prolyl hydroxylase inhibitor roxadustat suppresses chemoresistant glioblastoma growth by inducing ferroptosis.

Xiaodong Su, Yuan Xie, Junwen Zhang, Mingxin Li, Qing Zhang, Guishan Jin, Fusheng Liu.

Patients with glioblastoma (GBM) have poor prognosis and limited treatment options, largely due to therapy resistance upon the induction of apoptosis. Ferroptosis emerges as a potential antineoplastic strategy to bypass apoptosis resistance in traditional therapeutics. Hypoxia is a fundamental hallmark of GBM and hypoxia-inducible factor (HIF) is the main regulator of hypoxia response, however, the role of HIF has not been sufficiently explored in GBM. Herein, we first discovered that amplifying HIF signals by the prolyl hydroxylase (PHD) inhibitor roxadustat significantly suppressed GBM cell growth in vitro and in vivo, especially when the cells were resistant to temozolomide (TMZ). The accumulation of lipid peroxidation and cellular iron in GBM cells following roxadustat treatment indicated that the cells underwent ferroptosis, which was also supported by morphological changes in mitochondrial ultrastructure and immunogenic signals release. Moreover, in vivo studies further confirmed the ferroptosis induction and verified that roxadustat significantly prolonged survival of the mice harboring chemoresistant GBM without visible organ toxicity. Finally, we proved that the ferroptosis induction by roxadustat is HIF-α independent, especially activation of HIF-2α upregulating lipid regulatory genes was revealed to be mainly responsible for the enhanced lipid peroxidation. Altogether, our study provided novel evidence that amplifying HIF signals induced ferroptosis in chemoresistant GBM cells and suppressed the tumor growth in vivo, highlighting that ferroptosis induction by targeting HIF-α might provide new approaches to improve GBM treatment.

DOI: https://doi.org/10.1038/s41419-022-05304-8
Nat Commun. 2022 Oct 10. 13(1): 5971

ISG15 conjugation to proteins on nascent DNA mitigates DNA replication stress.

Christopher P Wardlaw, John H J Petrini.

The pathways involved in suppressing DNA replication stress and the associated DNA damage are critical to maintaining genome integrity. The Mre11 complex is unique among double strand break (DSB) repair proteins for its association with the DNA replication fork. Here we show that Mre11 complex inactivation causes DNA replication stress and changes in the abundance of proteins associated with nascent DNA. One of the most highly enriched proteins at the DNA replication fork upon Mre11 complex inactivation was the ubiquitin like protein ISG15. Mre11 complex deficiency and drug induced replication stress both led to the accumulation of cytoplasmic DNA and the subsequent activation of innate immune signaling via cGAS-STING-Tbk1. This led to ISG15 induction and protein ISGylation, including constituents of the replication fork. ISG15 plays a direct role in preventing replication stress. Deletion of ISG15 was associated with replication fork stalling, tonic ATR activation, genomic aberrations, and sensitivity to aphidicolin. These data reveal a previously unrecognized role for ISG15 in mitigating DNA replication stress and promoting genomic stability.

DOI: https://doi.org/10.1038/s41467-022-33535-y
EMBO J. 2022 Oct 10. e108040

Loss of ribonuclease DIS3 hampers genome integrity in myeloma by disrupting DNA:RNA hybrid metabolism.

Ilaria Gritti, Veronica Basso, Darawan Rinchai, Federica Corigliano, Silvia Pivetti, Marco Gaviraghi, Dalia Rosano, Davide Mazza, Sara Barozzi, Marco Roncador, Giovanni Parmigiani, Gaelle Legube, Dario Parazzoli, Davide Cittaro, Davide Bedognetti, Anna Mondino, Simona Segalla, Giovanni Tonon.

  The ribonuclease DIS3 is one of the most frequently mutated genes in the hematological cancer multiple myeloma, yet the basis of its tumor suppressor function in this disease remains unclear. Herein, exploiting the TCGA dataset, we found that DIS3 plays a prominent role in the DNA damage response. DIS3 inactivation causes genomic instability by increasing mutational load, and a pervasive accumulation of DNA:RNA hybrids that induces genomic DNA double-strand breaks (DSBs). DNA:RNA hybrid accumulation also prevents binding of the homologous recombination (HR) machinery to double-strand breaks, hampering DSB repair. DIS3-inactivated cells become sensitive to PARP inhibitors, suggestive of a defect in homologous recombination repair. Accordingly, multiple myeloma patient cells mutated for DIS3 harbor an increased mutational burden and a pervasive overexpression of pro-inflammatory interferon, correlating with the accumulation of DNA:RNA hybrids. We propose DIS3 loss in myeloma to be a driving force for tumorigenesis via DNA:RNA hybrid-dependent enhanced genome instability and increased mutational rate. At the same time, DIS3 loss represents a liability that might be therapeutically exploited in patients whose cancer cells harbor DIS3 mutations.

Keywords:  DNA damage repair; DNA:RNA Hybrids; R-loops; interferon; multiple myeloma

DOI:  https://doi.org/10.15252/embj.2021108040
Front Pharmacol. 2022 ;13 1019395

Editorial: Ferroptosis as new therapeutic targets in cancer: From molecular mechanisms to therapeutic opportunities.

Jian Chen, Xu Chen.



Keywords:  cancer therapy; ferroptosis; molecular mechanism; pharmacology; programmed cell death

DOI:  https://doi.org/10.3389/fphar.2022.1019395
Cancer Cell. 2022 Oct 10. pii: S1535-6108(22)00439-1. [Epub ahead of print]40(10): 1073-1076

A STING operation to expose KRAS and STK11 co-mutated lung cancers.

Ferdinandos Skoulidis, John V Heymach, Tina Cascone.

KRAS and STK11 (LKB1) co-mutated (KL) tumors define an immunologically cold and anti-PD-(L)1-refractory non-small-cell lung cancer (NSCLC) subset. In this issue of Cancer Cell, Kitajima et al. outline a strategy to unleash innate immunity in KL tumors by utilizing epigenetic de-repression of STING and pulsed inhibition of spindle assembly checkpoint kinase MPS1.

DOI: https://doi.org/10.1016/j.ccell.2022.09.010
Cancer Cell Int. 2022 Oct 11. 22(1): 309

Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres.

Jin-Kyoung Shim, Seonah Choi, Seon-Jin Yoon, Ran Joo Choi, Junseong Park, Eun Hee Lee, Hye Joung Cho, Suji Lee, Wan-Yee Teo, Ju Hyung Moon, Hyun Sil Kim, Eui Hyun Kim, Jae-Ho Cheong, Jong Hee Chang, Jong In Yook, Seok-Gu Kang.

  INTRODUCTION: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM.METHODS: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO.
RESULTS: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group.
CONCLUSION: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.

Keywords:  Etomoxir; Fatty acid oxidation; Glioblastoma; Temozolomide; Tumorsphere

DOI:  https://doi.org/10.1186/s12935-022-02731-7
Oncogene. 2022 Oct 14.

AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors.

Shanade Dunn, Cath Eberlein, Jason Yu, Albert Gris-Oliver, Swee Hoe Ong, Urs Yelland, Natalie Cureton, Anna Staniszewska, Robert McEwen, Millie Fox, James Pilling, Philip Hopcroft, Elizabeth A Coker, Patricia Jaaks, Mathew J Garnett, Beverley Isherwood, Violeta Serra, Barry R Davies, Simon T Barry, James T Lynch, Kosuke Yusa.

The PI3K pathway is commonly activated in breast cancer, with PI3K-AKT pathway inhibitors used clinically. However, mechanisms that limit or enhance the therapeutic effects of PI3K-AKT inhibitors are poorly understood at a genome-wide level. Parallel CRISPR screens in 3 PTEN-null breast cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3Kβ inhibitor). The dominant mechanism causing resistance is reactivated PI3K-AKT-mTOR signalling, but not other canonical signalling pathways. Deletion of TSC1/2 conferred resistance to PI3Kβi and AKTi through mTORC1. However, deletion of PIK3R2 and INPPL1 drove specific PI3Kβi resistance through AKT. Conversely deletion of PIK3CA, ERBB2, ERBB3 increased PI3Kβi sensitivity while modulation of RRAGC, LAMTOR1, LAMTOR4 increased AKTi sensitivity. Significantly, we found that Mcl-1 loss enhanced response through rapid apoptosis induction with AKTi and PI3Kβi in both sensitive and drug resistant TSC1/2 null cells. The combination effect was BAK but not BAX dependent. The Mcl-1i + PI3Kβ/AKTi combination was effective across a panel of breast cancer cell lines with PIK3CA and PTEN mutations, and delivered increased anti-tumor benefit in vivo. This study demonstrates that different resistance drivers to PI3Kβi and AKTi converge to reactivate PI3K-AKT or mTOR signalling and combined inhibition of Mcl-1 and PI3K-AKT has potential as a treatment strategy for PI3Kβi/AKTi sensitive and resistant breast tumours.

DOI: https://doi.org/10.1038/s41388-022-02482-9
Nat Chem Biol. 2022 Oct 13.

Targeting androgen receptor phase separation to overcome antiandrogen resistance.

Jingjing Xie, Hao He, Wenna Kong, Ziwen Li, Zhenting Gao, Daoqing Xie, Lin Sun, Xiaofei Fan, Xiangqing Jiang, Qiangang Zheng, Guo Li, Jidong Zhu, Guangya Zhu.

Patients with castration-resistant prostate cancer inevitably acquire resistance to antiandrogen therapies in part because of androgen receptor (AR) mutations or splice variants enabling restored AR signaling. Here we show that ligand-activated AR can form transcriptionally active condensates. Both structured and unstructured regions of AR contribute to the effective phase separation of AR and disordered N-terminal domain plays a predominant role. AR liquid-liquid phase separation behaviors faithfully report transcriptional activity and antiandrogen efficacy. Antiandrogens can promote phase separation and transcriptional activity of AR-resistant mutants in a ligand-independent manner. We conducted a phase-separation-based phenotypic screen and identified ET516 that specifically disrupts AR condensates, effectively suppresses AR transcriptional activity and inhibits the proliferation and tumor growth of prostate cancer cells expressing AR-resistant mutants. Our results demonstrate liquid-liquid phase separation as an emerging mechanism underlying drug resistance and show that targeting phase separation may provide a feasible approach for drug discovery.

DOI: https://doi.org/10.1038/s41589-022-01151-y