Crisafulli, Giovanni

Siravegna, Giulia

English

Institutional Research Information System University of Turin

Frontiers in OncologyOPEN ACCESSEDITED AND REVIEWED BYYun Dai,Peking University, China*CORRESPONDENCEGiovanni Crisafulligiovanni.crisafulli@unito.it;giovanni.crisafulli@ifom.euRECEIVED 17 July 2023ACCEPTED 27 July 2023PUBLISHED 08 August 2023CITATIONCrisafulli G and Siravegna G (2023)Editorial: The impact of geneticson CRC therapy: from adaptivemutability to drug resistance.Front. Oncol. 13:1260158.doi: 10.3389/fonc.2023.1260158COPYRIGHT© 2023 Crisafulli and Siravegna. This is anopen-access article distributed under theterms of the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums is permitted,provided the original author(s) and thecopyright owner(s) are credited and thatthe original publication in this journal iscited, in accordance with acceptedacademic practice. No use, distribution orreproduction is permitted which does notcomply with these terms.TYPE EditorialPUBLISHED 08 August 2023DOI 10.3389/fonc.2023.1260158Editorial: The impact of geneticson CRC therapy: from adaptivemutability to drug resistanceGiovanni Crisafulli 1* and Giulia Siravegna21IFOM ETS - The AIRC Institute of Molecular Oncology, Milan, Italy, 2Vidium Animal Health,Scottsdale, AZ, United StatesKEYWORDScancer evolution, genetics, genomics, drug resistance, target therapies, adaptivemutability, CRC (colorectal cancer)Editorial on the Research TopicThe impact of genetics on CRC therapy: from adaptive mutability todrug resistanceColorectal cancer (CRC) stands as one of the most common and lethal malignancies,contributing to approximately 9% of cancer-related deaths and 10% of all new cancerdiagnoses worldwide every year (1).The genetic landscape of CRC is characterized by a remarkable level of heterogeneity,which has been exploited to stratify patients into distinct tumour classes (2–4). In the era ofprecision oncology, the accurate stratification of patients based on their tumor’s geneticfeatures is crucial to guide effective therapeutic interventions (5). Even when targetedtherapies show to be effective in achieving an initial, partial response to the treatmentcausing tumour shrinkage, this response is often transitory (6–10). Indeed, after some time,resistance to targeted therapies occurs in virtually all cases (11–17).Tumors may harbor subpopulations of drug-resistant cells, which can survive underthe selective pressure of the drugs regimen. The existence of pre-existing resistant clonesposes a significant hurdle in achieving durable responses, underscoring the urgent need forthe discovery of novel strategies focused on promptly identifying and overcomingresistance right from the initiation of treatment (11–17). In addition to the presence ofpre-existing resistant clones, CRC tumour can also generate ex-novo resistance clonesthrough mechanisms of adaptive mutability (18–20) (Figure 1).It has been shown (21) that, under therapeutic pressure, tumour cells exhibit increasedmutational rates, thus facilitating the emergence of novel genetic alterations responsible fordrug resistance. This adaptive response allows the tumour to evade the effect of the targetedtherapy and continue proliferating, ultimately leading to treatment failure (18, 19, 21).Identifying the underlying mechanisms driving this adaptive mutability process is crucial todevelop effective strategies able to counteract the emergence and selection of resistant clones.In this special Research Topic, entitled “The impact of genetics on CRC therapy: fromadaptive mutability to drug resistance” the authors have focused on the role that the CRCgenetics plays on the therapy efficacy. Four research studies (Shailes et al.; Qin et al.; Luoet al.; Cai et al.), included in this special Research Topic, have shed light on different aspectsof colorectal cancer’s pathogenesis and provided insights into potential therapeuticfrontiersin.org01Crisafulli and Siravegna 10.3389/fonc.2023.1260158strategies, prognostic markers, and molecular mechanisms involvedin the disease progression and treatment response of CRC.Shailes et al. focused on identifying therapeutic strategies for thetreatment of CRC carrying APC mutations, which account fornearly 80% of all CRC cases and are also responsible for theinherited form of CRC (26, 27). They employed an APC mutantCRC cell line and CRISPR-cas9 gene editing approach to performan FDA-approved drug screen targeting over 1000 compounds. Asa result, they identified a statin, the HMG-CoA reductase inhibitor,as a potential therapeutic agent in APC mutant CRC. Statins havebeen demonstrated to induce a significant loss in cell viabilityspecifically in APC mutant cell lines and patient-derivedxenograft models. Importantly, Shailes et al. highlighted thesynthetic lethal relationship between APC mutations and thetreatment with statin, which could be further explored to treatother APC mutated cancer types, such as thyroid, brain cancer andpancreatic cancers (22). Identifying robust biomarkers anddeveloping novel technologies for early detection of resistance-associated genetic alterations may enable prompt modification oftherapeutic regimens, ensuring better patient outcomes.Within this context, the objective of the study of Qin et al. wasto investigate the association between genetic variations in genesinvolved in the immune regulation signaling and the clinicaloutcomes in metastatic colorectal cancer (mCRC) patients treatedwith bevacizumab-based chemotherapy, a well-established first-linetreatment in this setting. The authors genotyped specific single-nucleotide polymorphisms (SNPs) by using DNA from bloodsamples of 141 mCRC patients and identified the “AA” genotypeof rs2297136 in the CD274 gene to be correlated with betterprogression-free survival (PFS) and increased overall survival(OS), as opposed to patients harboring the “AG” or “GG”genotypes. These findings suggested that rs2297136 could serve asFrontiers in Oncology 02an important predictor for mCRC patients’ prognosis in the contextof bevacizumab-based chemotherapy.Another example of the importance of genetics for patients’stratification was reported by Luo et al. This study aimed atdeveloping a prognostic model based on cuproptosis-related genesin colon adenocarcinoma (COAD). Cuproptosis is a specific type ofcell death induced by an overload of copper ions in the cell (28).Through extensive data analysis of The Cancer Genome Atlas(TCGA) (2) and the Gene Expression Omnibus (GEO) databases,the authors generated a risk model comprising of five cuproptosis-related genes (CKDN2A, SDHB, CCS, ULK1, and CMC1), afterscreening for 30 differentially expressed genes from patients withCOAD. Based on this model, in both cohorts, the low-risk groupexhibited longer overall survival. The study also showed how changesin immune cells within the tumour microenvironment as a potentialmechanism underlying the prognostic implications of the risk model.In the last study published in the Research Topic, Cai et al.reported an integrative analysis investigating the role of pyroptosis-related long non-coding RNAs (PRLs) in CRC. Pyroptosis representsa form of cell death that is triggered by proinflammatory signals andassociated with inflammation (29). Using transcriptomic data fromTCGA (2) and external datasets, they constructed a risk modelcomprising eight PRLs (Z99289.2, FENDRR, CCDC144NL-ASL,TEX41, MNX1-AS1, NKILA, LINC02798, and LINC02381).These PRLs were stratified into two molecular subtypes involvedin immune modulators, immune infiltration of tumor immunemicroenvironment, and inflammatory pathways, and threeindependent methods were applied to predict PRL-relatedsensitivity to chemotherapeutic drugs. This, together with theability of predicting treatment response and prognosis, are majorcontributors to a better understanding of CRC overall pathogenesisand the development of effective immunotherapy regimens.BAFIGURE 1(A) Primary resistance to cancer therapy model due to pre-existing, drug insensitive tumour clones. (B) Adaptive mutability model of acquiredresistance to cancer therapy. Figure created with BioRender.comfrontiersin.orgCrisafulli and Siravegna 10.3389/fonc.2023.1260158In summary, it is now well acknowledged how theunderstanding of the genetic mechanisms underlying drugresistance is fundamental to improve precision oncology strategiesin CRC patients. Among other cancer types, CRC presents one ofthe most complex genetic landscapes, characterized by highlyheterogeneous tumour subpopulations, making it even morechallenging to find the optimal targeted therapy and extendoverall survival. Advancing our understanding of the mechanismsdriving the emergence and selection of resistance clones throughspecific mechanisms of cell death [pyroptosis or cuproptosis whichare apparently different from apoptosis, necroptosis, and ferroptosis(30)] is crucial to develop effective precision oncology strategies, asaddressed by this special Research Topic. Further investigations andvalidations are warranted to translate these findings into clinicalpractice, with the ultimate goal of improving patient’s outcome.In this special Research Topic, the authors considered theimpact of genetics and transcriptomics in CRC. Further studiesshould focus on the integration of genomic profiling with otheromics, immune infiltration of tumor microenvironment and thedynamic monitoring of tumour evolution during novelcombination therapies, all of which hold promises in fighting theemergence of resistance and maximizing treatment efficacy.Furthermore, the study of adaptive mutagenesis in the context ofcolorectal cancer therapy is still in its early stages. However, thepotential to develop novel drugs that could target the modulation ofmutational rates is promising. By impeding the cancer cells’adaptive capability, we can potentially prevent the emergence ofresistant clones and pave the way for more effective and durabletreatment strategies. Continued research and exploration of thisFrontiers in Oncology 03field are vital for advancing our understanding and transformingthe landscape of colorectal cancer therapy.Author contributionsGC: Conceptualization, Resources, Supervision, Writing – originaldraft, Writing – review & editing. GS: Resources, Supervision,Writing –original draft, Writing – review & editing, Conceptualization.Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.The authors declared that they were an editorial board memberof Frontiers, at the time of submission. This had no impact on thepeer review process and the final decision.Publisher’s noteAll claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.References1. Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, Harvey JD, et al. Cancerincidence, mortality, years of life lost, years lived with disability, and disability-adjustedlife years for 29 cancer groups from 2010 to 2019: A systematic analysis for the globalburden of disease study 2019. JAMA Oncol (2022) 8:420–44. doi: 10.1001/jamaoncol.2021.69872. C. G. A. Network. Comprehensive molecular characterization of human colonand rectal cancer. Nature (2012) 487:330–7. doi: 10.1038/nature112523. Jiricny J. The multifaceted mismatch-repair system. Nat Rev Mol Cell Biol (2006)7:335–46. doi: 10.1038/nrm19074. Sinicrope FA, Sargent DJ. Molecular pathways: microsatellite instability incolorectal cancer: prognostic, predictive, and therapeutic implications. Clin CancerRes (2012) 18:1506–12. doi: 10.1158/1078-0432.CCR-11-14695. Punt CJ, Koopman M, Vermeulen L. From tumour heterogeneity to advances inprecision treatment of colorectal cancer. Nat Rev Clin Oncol (2017) 14:235–46. doi:10.1038/nrclinonc.2016.1716. Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F,et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory,KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer(HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. LancetOncol (2016) 17:738–46. doi: 10.1016/S1470-2045(16)00150-97. Siravegna G, Lazzari L, Crisafulli G, Sartore-Bianchi A, Mussolin B, Cassingena A,et al. Radiologic and genomic evolution of individual metastases during HER2 blockade incolorectal cancer. Cancer Cell (2018) 34:148–162.e147. doi: 10.1016/j.ccell.2018.06.0048. Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, et al.Encorafenib, binimetinib, and cetuximab in. N Engl J Med (2019) 381:1632–43. doi:10.1056/NEJMoa19080759. Mauri G, Bonazzina E, Amatu A, Tosi F, Bencardino K, Gori V, et al. Theevolutionary landscape of treatment for. Cancers (Basel) (2021) 13(1):137. doi: 10.3390/cancers1301013710. Siena S, Di Bartolomeo M, Raghav K, Masuishi T, Loupakis F, Kawakami H,et al. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastaticcolorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. LancetOncol (2021) 22:779–89. doi: 10.1016/S1470-2045(21)00086-311. Arena S, Siravegna G, Mussolin B, Kearns JD, Wolf BB, Misale S, et al. MM-151overcomes acquired resistance to cetuximab and panitumumab in colorectal cancersharboring EGFR extracellular domain mutations. Sci Transl Med (2016) 8:324ra314.doi: 10.1126/scitranslmed.aad564012. Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, et al.Amplification of the MET receptor drives resistance to anti-EGFR therapies incolorectal cancer. Cancer Discovery (2013) 3:658–73. doi: 10.1158/2159-8290.CD-12-055813. Misale S, Arena S, Lamba S, Siravegna G, Lallo A, Hobor S, et al. Blockade ofEGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer. Sci Transl Med (2014) 6:224ra226. doi: 10.1126/scitranslmed.300794714. Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, et al. Emergenceof KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.Nature (2012) 486:532–6. doi: 10.1038/nature1115615. Oddo D, Sennott EM, Barault L, Valtorta E, Arena S, Cassingena A, et al.Molecular landscape of acquired resistance to targeted therapy combinations in BRAF-mutant colorectal cancer. Cancer Res (2016) 76:4504–15. doi: 10.1158/0008-5472.CAN-16-039616. Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, et al.Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancerpatients. Nat Med (2015) 21:795–801. doi: 10.1038/nm.387017. Van Emburgh BO, Arena S, Siravegna G, Lazzari L, Crisafulli G, Corti G, et al.Acquired RAS or EGFR mutations and duration of response to EGFR blockade incolorectal cancer. Nat Commun (2016) 7:13665. doi: 10.1038/ncomms13665frontiersin.orgCrisafulli and Siravegna 10.3389/fonc.2023.126015818. Russo M, Crisafulli G, Sogari A, Reilly NM, Arena S, Lamba S, et al. Adaptivemutability of colorectal cancers in response to targeted therapies. Science (2019)366:1473–80. doi: 10.1126/science.aav447419. Cipponi A, Goode DL, Bedo J, McCabe MJ, Pajic M, Croucher DR, et al. MTORsignaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution incancer. Science (2020) 368:1127–31. doi: 10.1126/science.aau876820. Russo M, Sogari A, Bardelli A. Adaptive evolution: how bacteria and cancer cellssurvive stressful conditions and drug treatment. Cancer Discovery (2021) 11:1886–95.doi: 10.1158/2159-8290.CD-20-158821. Russo M, Pompei S, Sogari A, Corigliano M, Crisafulli G, Puliafito A, et al. Amodified fluctuation-test framework characterizes the population dynamics andmutation rate of colorectal cancer persister cells. Nat Genet (2022) 54:976–84. doi:10.1038/s41588-022-01105-z22. Shailes H, Tse WY, Freitas MO, Silver A, Martin SA. Statin treatment as atargeted therapy for APC-mutated colorectal cancer. Front Oncol (2022) 12:880552.doi: 10.3389/fonc.2022.88055223. Qin W, Zhao B, Wang D, Liu J, Zhou Y, ZhuW, et al. A genetic variant in. FrontOncol (2022) 12:922342. doi: 10.3389/fonc.2022.922342Frontiers in Oncology 0424. Luo B, Lin J, Ni A, Cai W, Yu X, Wang M, et al. A novel defined cuproptosis-related gene signature for predicting the prognosis of colon adenocarcinoma. FrontOncol (2022) 12:927028. doi: 10.3389/fonc.2022.92702825. Cai X, Liang X, Wang K, Liu Y, Hao M, Li H, et al. Pyroptosis-related lncRNAs:A novel prognosis signature of colorectal cancer. Front Oncol (2022) 12:983895. doi:10.3389/fonc.2022.98389526. Sinicrope FA. Lynch syndrome-associated colorectal cancer. N Engl J Med(2018) 379:764–73. doi: 10.1056/NEJMcp171453327. Balmaña J, Balaguer F, Cervantes A, Arnold DE. G. W. Group. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol (2013) 24(Suppl 6):vi73–80. doi: 10.1093/annonc/mdt20928. Xie J, Yang Y, Gao Y, He J. Cuproptosis: mechanisms and links with cancers.Mol Cancer (2023) 22:46. doi: 10.1186/s12943-023-01732-y29. Nirmala JG, Lopus M. Cell death mechanisms in eukaryotes. Cell Biol Toxicol(2020) 36:145–64. doi: 10.1007/s10565-019-09496-230. Tsvetkov P, Detappe A, Cai K, Keys HR, Brune Z, Ying W, et al. Mitochondrialmetabolism promotes adaptation to proteotoxic stress. Nat Chem Biol (2019) 15:681–9.doi: 10.1038/s41589-019-0291-9frontiersin.org

Editorial: The impact of genetics on CRC therapy: from adaptive mutability to drug resistance

https://iris.unito.it/bitstream/2318/2010330/1/fonc-13-1260158.pdf

Editorial: The impact of genetics on CRC therapy: from adaptive mutability to drug resistance

Abstract

Similar works

Full text

Available Versions

Institutional Research Information System University of Turin