Hou, Weilong

Wang, Haitao

Wang, Rui-Hong

Wong, Ada Hang-Heng

Zhou, Jian-Guo

Frontiers in Genetics

PubMed

Wang, Haitao

Wang, Rui-Hong

Zhou, Jian-Guo

Hou, Weilong

Wong, Ada Hang-Heng

PubMed Central

Editorial: Uncovering Drug Resistance During Cancer Therapy

OPEN FAU Online-Publikationssystem der Friedrich-Alexander-Universität Erlangen-Nürnberg

Editorial: Uncovering Drug ResistanceDuring Cancer TherapyHaitao Wang1*, Rui-Hong Wang1, Jian-Guo Zhou2,3,4,5, Weilong Hou1 andAda Hang-Heng Wong6*1Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (NIH), Bethesda, MA, United States,2Department of Oncology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, China, 3Translational Radiobiology,Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany, 4Department of Radiation Oncology,Universitätsklinikum Erlangen, Erlangen, Germany, 5Comprehensive Cancer Center Erlangen-Europäische MetropolregionNürnberg (EMN), Erlangen, Germany, 6AW Medical Co Ltd, Macao, Macao SAR, ChinaKeywords: cancer, oncology, cancer therapy, drug resistance, next generation sequencing, biomarkersEditorial on the Research TopicUncovering Drug Resistance During Cancer TherapyDrug resistance is one of the most difficult problems to tackle during cancer therapy because of itsmultifaceted nature (Vasan, Baselga et al., 2019). Innate drug resistance is generally caused by cancerheterogeneity, and is further complicated by the uniquemicroenvironment and immune landscape of eachindividual patient. On the other hand, acquired resistance is primarily induced by treatment. The interplayamong cancer, its microenvironment and the immune system during the course of treatment unveils thecontinuous evolution of drug resistance on the temporal scale. Furthermore, the diverse mechanisms ofanti-cancer drugs, from targeting cancer proliferation to immune evasion, often trigger drug resistance viadistinct courses. Hence, continuous disease monitoring and multi-timepoint sampling becameindispensable to interrogate cancer progression and resistance development over the course of treatment.In this issue, we discussed the molecular mechanisms of drug resistance during cancer therapy. Drivermutations have long been considered the mainstream mechanism of drug resistance development. Forinstance, the development of RASmutations to constitutively activate the EGFR/RAS pathway is often seenwithinweeks during anti-EGFR treatment.However, elucidation of pointmutations is insufficient to decipherthe cancer landscape, let alone the tumor microenvironment. The advent of sequencing technologies enablesbroader genome coverage and greater depths to uncover genetic mutations other than point mutations, suchas indels and copy number changes, while development of novel sequencing methodologies providesadditional information on epigenetic modifications, transcriptional regulation, and so on.For example, Huang et al., described how the membrane transporter SLC15A4 could serve as aprognostic biomarker for lung adenocarcinoma patients, even though themutation rate of SLC15A familymembers is relatively low. This underscores how the increased expression of a transmembrane peptidetransporter (Song, Hu et al., 2018) that functions in mTOR-dependent autoantibody production(Kobayashi, Shimabukuro-Demoto et al., 2014) could indicate prognosis. While the basal level ofSLC15A4 is prognostic,Wei et al., demonstrated thatMX2 is upregulatedwith increasing cancer stage andafter renal cell carcinoma cells develop resistance against the anti-angiogenic drug Sunitinib. Prognosticbiomarkers do not always correlate with tumorigenesis or cancer progression, but might be by-productsof these processes. Pretreatment prognosis suggests innate drug resistance, whereas on-treatmentprognosis suggests the development of acquired resistance.Aside from mRNA expression, microRNAs also play important roles in cancer drug resistance (Si,Shen et al., 2019). Tang et al., described how themicroRNAprocessing protein encoded by hnRNPA2B1 isupregulated in colon cancer to promote cancer progression via theMAPK pathway. Zheng et al., depictedseveral microRNAs that are positively correlated toMSMO 1 expression, which is positively correlated totumor burden and poor prognosis in cervical squamous cell carcinoma. To date, microRNAs contributeEdited and reviewed by:Zhe-Sheng Chen,St. John’s University, United States*Correspondence:Haitao Wanghaitao.wang@nih.govAda Hang-Heng Wongsynxin2008@gmail.comSpecialty section:This article was submitted toCancer Genetics and Oncogenomics,a section of the journalFrontiers in GeneticsReceived: 17 May 2022Accepted: 23 June 2022Published: 19 July 2022Citation:Wang H, Wang R-H, Zhou J-G, Hou Wand Wong AH-H (2022) Editorial:Uncovering Drug Resistance DuringCancer Therapy.Front. Genet. 13:945842.doi: 10.3389/fgene.2022.945842Frontiers in Genetics | www.frontiersin.org July 2022 | Volume 13 | Article 9458421EDITORIALpublished: 19 July 2022doi: 10.3389/fgene.2022.945842to cancer drug resistance mainly through regulation of geneexpression. While some microRNAs directly bind tocomplementary mRNAs to silence gene expression, otherscooperate with long non-coding RNAs to fine tune gene expression.The mechanisms of drug resistance are nonetheless related to thetype of anti-cancer drug. While broad-spectrum chemotherapy andtargeted therapy inadvertently focus on pathways related to cancerproliferation, sole characterization of cancer cells would leave outimportant players in the tumormicroenvironment that are critical tothe development of drug resistance towards immunotherapy. Eventhough these players may or may not be direct targets ofimmunotherapy, they contribute to the success ofimmunotherapy. Wang et al., reviewed various mechanisms ofimmunotherapy resistance in glioblastoma, such as the infiltrationof M2-type tumor-assoicated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). TAMs are suggested to promotedrug resistance bymodulating the cancer stem cell (CSC) populationand suppress the immune system via interactions with cytotoxic andregulatory T cells (Petty and Yang 2017). On the other hand,polymorphonuclear MDSCs, which represents 80% of all MDSCsin the majority of cancer types, mainly suppress T cells (Gabrilovich2017). Hence, cancer evolves to recruit the host immune system tocounteract the effects of immunotherapy. Other non-immuneplayers include cancer-associated fibroblasts (CAFs) that secretegrowth factors and cytokines to promote tumor growth in breastcancer (Cosentino, Plantamura et al., 2021). Unequivocably,investigation of the tumor microenvironment and the immune-oncological crosstalk is critical to broaden our understanding of themechanisms of acquired drug resistance.Therefore, novel sequencing technologies based on single cellsand in situ hybridization are developed. These technologies providedetails to identify and characterize the tumor microenvironmentwith unprecedented resolution in terms of cell type and spatiallocalization. Nevertheless, the enhanced resolution also posits newfeasibility problems during clinical translation because it isimpossible for any physician to interpret an innumerable list ofbiomarkers to their patients. Hence, dimensionality reduction by theapplication of ratiometric parameters comes into play. For example,Wang et al., used the ratio of SIRT4/SIRT6 mRNA expression toserve as prognostic biomarkers for serous ovarian cancer.While bothSIRT4 and SIRT6 are histone deacetelylases of the sirtuin family,SIRT4 acts as a tumor suppressor to repress glutamine metabolism(Csibi, Fendt et al., 2013; Jeong, Xiao et al., 2013), a key energy sourcefor cancer cells, whereas SIRT6 exhibits context-dependentpleiotropic roles in cancer (Fiorentino, Carafa et al., 2021). Thecombination of these two biomarkers with potentially contrastingroles but are functionally linked succeeds in dimensionalityreduction. Alternatively, artificial intelligence and computationalvisualization aids in interpreting complex results, but the inclinico application of these methods remains afar.In conclusion, our understanding of the mechanisms of cancerdrug resistance has been consistently broadening and deepeningby the advancement of novel technologies and methodologiesthat no longer limits to genetics, but also encompasses epigeneticand transcriptional mechanisms. We foresee that futureintegration of omic technologies will further expands ourunderstanding of cancer drug resistance.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct, andintellectual contribution to the work and approved it forpublication.REFERENCESCosentino, G., Plantamura, I., Tagliabue, E., Iorio, M. V., and Cataldo, A. (2021).Breast Cancer Drug Resistance: Overcoming the Challenge by Capitalizing onMicroRNA and Tumor Microenvironment Interplay. Cancers (Basel) 13 (15),3691. doi:10.3390/cancers13153691Csibi, A., Fendt, S.-M., Li, C., Poulogiannis, G., Choo, A. Y., Chapski, D. J., et al. (2013).The mTORC1 Pathway Stimulates GlutamineMetabolism and Cell Proliferation byRepressing SIRT4. Cell 153 (4), 840–854. doi:10.1016/j.cell.2013.04.023Fiorentino, F., Carafa,V., Favale,G.,Altucci, L.,Mai,A., andRotili,D. (2021). TheTwo-FacedRole of SIRT6 in Cancer. Cancers (Basel) 13 (5), 1156. doi:10.3390/cancers13051156Gabrilovich, D. I. (2017). Myeloid-Derived Suppressor Cells. Cancer Immunol. Res.5 (1), 3–8. doi:10.1158/2326-6066.cir-16-0297Jeong, S. M., Xiao, C., Finley, L. W. S., Lahusen, T., Souza, A. L., Pierce, K., et al.(2013). SIRT4 Has Tumor-Suppressive Activity and Regulates the CellularMetabolic Response to DNA Damage by Inhibiting Mitochondrial GlutamineMetabolism. Cancer Cell 23 (4), 450–463. doi:10.1016/j.ccr.2013.02.024Kobayashi, T., Shimabukuro-Demoto, S., Yoshida-Sugitani, R., Furuyama-Tanaka, K.,Karyu, H., Sugiura, Y., et al. (2014). The Histidine Transporter SLC15A4 CoordinatesmTOR-dependent Inflammatory Responses and Pathogenic Antibody Production.Immunity 41 (3), 375–388. doi:10.1016/j.immuni.2014.08.011Petty, A. J., and Yang, Y. (2017). Tumor-associatedMacrophages: Implications in CancerImmunotherapy. Immunotherapy 9 (3), 289–302. doi:10.2217/imt-2016-0135Si, W., Shen, J., Zheng, H., and Fan, W. (2019). The Role and Mechanisms ofAction of microRNAs in Cancer Drug Resistance. Clin. Epigenet 11 (1), 25.doi:10.1186/s13148-018-0587-8Song, F., Hu, Y., Wang, Y., Smith, D. E., and Jiang, H. (2018). FunctionalCharacterization of Human Peptide/Histidine Transporter 1 in StablyTransfected MDCK Cells. Mol. Pharm. 15 (2), 385–393. doi:10.1021/acs.molpharmaceut.7b00728Vasan, N., Baselga, J., and Hyman, D. M. (2019). A View on Drug Resistance inCancer. Nature 575 (7782), 299–309. doi:10.1038/s41586-019-1730-1Conflict of Interest: AW is a founder and shareholder of AW Medical Co Ltd.The remaining authors declare that the research was conducted in the absence ofany commercial or financial relationships that could be construed as a potentialconflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofthe publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2022Wang,Wang, Zhou, Hou andWong. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Genetics | www.frontiersin.org July 2022 | Volume 13 | Article 9458422Wang et al. Editorial: Drug Resistance and Cancer

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Editorial: Uncovering Drug Resistance During Cancer Therapy

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