bims-cadres 2022-10-23 papers

Issue of 2022–10–23
seven papers selected by
Rana Gbyli, Yale University

Sci Signal. 2022 Oct 18. 15(756): eabj3490

Rerouting the drug response: Overcoming metabolic adaptation in KRAS-mutant cancers.

Deborah Y Moss, Christopher McCann, Emma M Kerr.

Mutations in guanosine triphosphatase KRAS are common in lung, colorectal, and pancreatic cancers. The constitutive activity of mutant KRAS and its downstream signaling pathways induces metabolic rewiring in tumor cells that can promote resistance to existing therapeutics. In this review, we discuss the metabolic pathways that are altered in response to treatment and those that can, in turn, alter treatment efficacy, as well as the role of metabolism in the tumor microenvironment (TME) in dictating the therapeutic response in KRAS-driven cancers. We highlight metabolic targets that may provide clinical opportunities to overcome therapeutic resistance and improve survival in patients with these aggressive cancers.

DOI: https://doi.org/10.1126/scisignal.abj3490

Cell Death Dis. 2022 Oct 15. 13(10): 871

Loss of CASZ1 tumor suppressor linked to oncogenic subversion of neuroblastoma core regulatory circuitry.

Zhihui Liu, Xiyuan Zhang, Man Xu, Haiyan Lei, Jack F Shern, Carol J Thiele.

The neural crest lineage regulatory transcription factors (TFs) form a core regulatory circuitry (CRC) in neuroblastoma (NB) to specify a noradrenergic tumor phenotype. Oncogenic subversion of CRC TFs is well documented, but the role of loss of tumor suppressors plays remains unclear. Zinc-finger TF CASZ1 is a chromosome 1p36 (chr1p36) tumor suppressor. Single-cell RNA sequencing data analyses indicate that CASZ1 is highly expressed in developing chromaffin cells coincident with an expression of NB CRC TFs. In NB tumor cells, the CASZ1 tumor suppressor is silenced while CRC components are highly expressed. We find the NB CRC component HAND2 directly represses CASZ1 expression. ChIP-seq and transcriptomic analyses reveal that restoration of CASZ1 upregulates noradrenergic neuronal genes and represses expression of CRC components by remodeling enhancer activity. Our study identifies that the restored CASZ1 forms a negative feedback regulatory circuit with the established NB CRC to induce noradrenergic neuronal differentiation of NB.

DOI: https://doi.org/10.1038/s41419-022-05314-6

Front Oncol. 2022 ;12 887068

ITGB5 promotes innate radiation resistance in pancreatic adenocarcinoma by promoting DNA damage repair and the MEK/ERK signaling pathway.

Xin Wen, Si Chen, Xueting Chen, Hui Qiu, Wei Wang, Nie Zhang, Wanming Liu, Tingting Wang, Xin Ding, Longzhen Zhang.

Pancreatic adenocarcinoma (PAAD) is one of the most aggressive digestive system tumors in the world, with a low early diagnosis rate and a high mortality. Integrin beta 5 (ITGB5) is demonstrated to be a potent tumor promoter in several carcinomas. However, it is unknown whether ITGB5 participates in the occurrence and development of PAAD. In this study, we confirmed a high expression of ITGB5 in PAAD and its role in promoting invasiveness and transitivity in PAAD. Besides, the knockdown of ITGB5 increased cell sensitivity to radiation by promoting DNA damage repair and the MEK/ERK signaling pathway. Collectively, these results show that ITGB5 plays an essential role in pancreatic cancer growth and survival.

Keywords: DNA damage repair; ITGB5; MEK/ERK signaling pathway; pancreatic adenocarcinoma (PAAD); radio-sensitivity

DOI: https://doi.org/10.3389/fonc.2022.887068

Biochimie. 2022 Oct 13. pii: S0300-9084(22)00268-1. [Epub ahead of print]

Autophagy: Dual roles and perspective for clinical treatment of colorectal cancer.

Yabin Zhang, Haiyan Li, Liang Lv, Kefeng Lu, Huihui Li, Wenli Zhang, Tao Cui.

Colorectal cancer (CRC) raises concerns to people because of its high recurrence and metastasis rate, diagnosis challenges, and poor prognosis. Various studies have shown the association of altered autophagy with tumorigenesis, tumor-stroma interactions, and resistance to cancer therapy in CRC. Autophagy is a highly conserved cytosolic catabolic process in eukaryotes that plays distinct roles in CRC occurrence and progression. In early tumorigenesis, autophagy may inhibit tumor growth through diverse mechanisms, whereas it exhibits a tumor promoting function in CRC progression. This different functions of autophagy in CRC occurrence and progression make developing therapies targeting autophagy complicated. In this review, we discuss the classification and process of autophagy as well as its dual roles in CRC, functions in the tumor microenvironment, cross-talk with apoptosis, and potential usefulness as a CRC therapeutic target.

Keywords: Autophagy; Chemo-/immuno-therapy; Colorectal cancer; Tumor microenvironment; Tumor promoter; Tumor suppressor

DOI: https://doi.org/10.1016/j.biochi.2022.10.004

Nat Commun. 2022 Oct 18. 13(1): 6163

Genome-wide functional screening of drug-resistance genes in Plasmodium falciparum.

Shiroh Iwanaga, Rie Kubota, Tsubasa Nishi, Sumalee Kamchonwongpaisan, Somdet Srichairatanakool, Naoaki Shinzawa, Din Syafruddin, Masao Yuda, Chairat Uthaipibull.

The global spread of drug resistance is a major obstacle to the treatment of Plasmodium falciparum malaria. The identification of drug-resistance genes is an essential step toward solving the problem of drug resistance. Here, we report functional screening as a new approach with which to identify drug-resistance genes in P. falciparum. Specifically, a high-coverage genomic library of a drug-resistant strain is directly generated in a drug-sensitive strain, and the resistance gene is then identified from this library using drug screening. In a pilot experiment using the strain Dd2, the known chloroquine-resistant gene pfcrt is identified using the developed approach, which proves our experimental concept. Furthermore, we identify multidrug-resistant transporter 7 (pfmdr7) as a novel candidate for a mefloquine-resistance gene from a field-isolated parasite; we suggest that its upregulation possibly confers the mefloquine resistance. These results show the usefulness of functional screening as means by which to identify drug-resistance genes.

DOI: https://doi.org/10.1038/s41467-022-33804-w

Pharmacol Res. 2022 Oct 14. pii: S1043-6618(22)00460-1. [Epub ahead of print] 106514

Down-regulating Nrf2 by tangeretin reverses multiple drug resistance to both chemotherapy and EGFR tyrosine kinase inhibitors in lung cancer.

Ying Xie, Sen-Ling Feng, Fang He, Pei-Yu Yan, Xiao-Jun Yao, Xing-Xing Fan, Elaine Lai-Han Leung, Hua Zhou.

Multiple drug resistance (MDR) is the major obstacle for both chemotherapy and molecular-targeted therapy for cancer, which is mainly caused by overexpression of ABC transporters or genetic mutation of drug targets. Based on previous studies, we hypothesized that ROS/Nrf2 is the common target for overcoming acquired drug resistance to both targeted therapy and chemotherapy treatments. In this study, we firstly proved that the levels of ROS and Nrf2 were remarkably up-regulated in both H1975 (Gefitinib-resistant lung cancer cells with T790M) and A549/T (paclitaxel-resistant) cells, which is consistent with the clinical database analysis results of lung cancer patients that Nrf2 expression level is negatively related to survival rate. Nrf2 Knockdown with siRNA or tangeretin (TG, a flavonoid isolated from citrus peels) inhibited the MDR cell growth by suppressing the Nrf2 pathway, and efficiently enhanced the anti-tumor effects of paclitaxel and AZD9291 (the third generation of TKI) in A549/T or H1975, respectively. Moreover, TG sensitized A549/T cells-derived xenografts to paclitaxel via inhibiting Nrf2 and its downstream target P-gp, leading to an increased paclitaxel concentration in tumors. Collectively, targeting Nrf2 to enhance ROS may be a common target for overcoming the acquired drug resistance and enhancing the therapeutic effects of chemotherapy and molecular-targeted therapy.

Keywords: Drug resistance; EGFR tyrosine kinase inhibitors; Nrf2; chemotherapy; tangeretin

DOI: https://doi.org/10.1016/j.phrs.2022.106514