On 13-14 February, the EACR held our virtual conference, Signaling Circuits in Cancer, where over 100 scientists from 28 countries gathered to discuss our global understanding of how cancer cell signaling circuits are controlled, and how they determine cancer progression and therapy resistance. In case you missed it, the EACR’s Scientific Officer, Dr. Alexandra Boitor, shares here the scientific highlights.
Kinases and phosphatases: from cancer progression to drug development
Two focal points for discussion during the conference were the CDK and the MAPK/ERK pathways. The emerging role of CDK12 as a potential target for anti-cancer treatments was highlighted by Stephin Vervoort, who discussed the role of CDK12 in controlling global RNA polymerase II processivity [1]. EACR members, you can watch Stephin’s talk in our On-demand Video Archive by logging in here.
The involvement of several players that act on the ERK/MAPK pathway was considered by several speakers in their presentations. Mutsuhiro Takekawa looked at the involvement of ERK pathway and PP2A in tumour progression by increasing the expression of immediate-early genes [2]. Michelle Arkin focused her presentation on modulating MAPK pathway (C-RAF activity) by using molecular glues to target 14-3-3 protein-protein interactions [3,4].
You can watch Michelle Arkin’s talk on the EACR’s YouTube channel:
Cancer Cell Plasticity: Persister Cells
In her presentation, Mariangela Russo linked MAPK pathway inhibitors and other targeted therapies to a time and dose-dependent increase of DNA damage in drug-tolerant persister cells, unavailing a vulnerability that could be exploited for improving cancer treatments [5]. You can rewatch her talk in the EACR members’ On-Demand Video Archive. Building on her recent findings regarding persister cell lineages and metabolism [6], Yaara Oren presented some very new and exciting, unpublished data from her lab looking at persister cells’ ability to resist treatment and retain a memory of prior drug exposure. In his presentation, Jukka Westermarck focused on the transition of dormant drug-tolerant cells to re-proliferating cells in HER2+ breast cancer under tyrosine kinase inhibitors therapy, providing the first transcriptional landscape of this process and identifying a new druggable target to overcome tyrosine kinase inhibitors resistance [7].
Overcoming Drug Resistance
Talks at this conference also covered two main approaches to overcoming or delaying drug resistance and persistence. Gad Getz’s presentation focused on the identification of vulnerabilities of resistant cells that could potentially be targeted through therapy. Dr Getz’s presentation focused on the detection of convergent evolution in tumoral tissue by generating rich phylogenetic trees and the assessment of downstream effects of the resistance mutations [8,9]. Jean-Emmanuel Sarry directed his attention towards combinatorial therapy. With a focus on the role of mitochondrial oxidative metabolism in disease relapse in acute myeloid leukemia, Sarry’s research provides a rationale for targeting mitochondrial metabolism to enhance the efficacy of chemotherapy in acute myeloid leukemia [10].
Bernhard Kuster presented proteome-wide technologies that measure target deconvolution, pathway engagement and cellular reprogramming in a dose-dependent manner. These technologies were employed by Kuster and his team to characterise responses to a variety of cancer treatments which uncovered surprising findings including drug repurposing opportunities [11,12].
In summary
The scientific programme committtee, Jukka Westermarck (Finland), Chiara Ambrogio (Italy) and Yaara Oren (Israel), put together an outstanding programme for the scientists in academia and industry interested in the most recent developments in non-genetic signaling mechanisms and their roles in cancer progression and therapy resistance. With a focus on the mechanistic aspects of post-translational and transcriptional regulation and large OMICS-based global understanding of cancer cell signaling circuits, the conference covered a variety of topics including mechanistic insights into the mode of action of several kinases and phosphatases, transcriptional and epigenetic gene regulation, non-genetic signaling rewiring, cancer cell plasticity and proteogenomic signal integration.
EACR Conferences
At the EACR we are dedicated to providing excellent cancer research conferences where the latest research topics and interaction for participants are the very highest priorities. Make sure you add the dates of the upcoming EACR Conferences to your diary now. Don’t forget we offer member discounts on all of our registration fees!
References:
[1] Fan Z, Devlin JR, Hogg SJ, Doyle MA, Harrison PF, Todorovski I, Cluse LA, Knight DA, Sandow JJ, Gregory G, Fox A, Beilharz TH, Kwiatkowski N, Scott NE, Vidakovic AT, Kelly GP, Svejstrup JQ, Geyer M, Gray NS, Vervoort SJ, Johnstone RW. CDK13 cooperates with CDK12 to control global RNA polymerase II processivity. Sci Adv. 2020 Apr 29;6(18):eaaz5041. doi: 10.1126/sciadv.aaz5041. PMID: 32917631; PMCID: PMC7190357.
[2] Ohe S, Kubota Y, Yamaguchi K, Takagi Y, Nashimoto J, Kozuka-Hata H, Oyama M, Furukawa Y, Takekawa M. ERK-mediated NELF-A phosphorylation promotes transcription elongation of immediate-early genes by releasing promoter-proximal pausing of RNA polymerase II. Nat Commun. 2022 Dec 3;13(1):7476. doi: 10.1038/s41467-022-35230-4. PMID: 36463234; PMCID: PMC9719515.
[3] Dyana N. Kenanova, Emira J. Visser, Johanna M. Virta, Eline Sijbesma, Federica Centorrino, Holly R. Vickery, Mengqi Zhong, R. Jeffrey Neitz, Luc Brunsveld, Christian Ottmann, and Michelle R. Arkin, ACS Central Science 2023 9 (5), 937-946
DOI: 10.1021/acscentsci.2c01449
[4] Vickery, H.R., Virta, J.M., Konstantinidou, M. and Arkin, M.R., 2024. Development of a NanoBRET assay for evaluation of 14-3-3σ molecular glues. bioRxiv, pp.2023-12.
[5] Russo, M., Pompei, S., Sogari, A., Corigliano, M., Crisafulli, G., Puliafito, A., Lamba, S., Erriquez, J., Bertotti, A., Gherardi, M. and Di Nicolantonio, F., 2022. A modified fluctuation-test framework characterizes the population dynamics and mutation rate of colorectal cancer persister cells. Nature Genetics, 54(7), pp.976-984.
[6] Oren, Y., Tsabar, M., Cuoco, M.S., Amir-Zilberstein, L., Cabanos, H.F., Hütter, J.C., Hu, B., Thakore, P.I., Tabaka, M., Fulco, C.P. and Colgan, W., 2021. Cycling cancer persister cells arise from lineages with distinct programs. Nature, 596(7873), pp.576-582.
[7] Momeny, M., Tienhaara, M., Chakroborty, D., Sharma, M., Varjus, R., Merisaari, J., Padzik, A., Vogt, A., Paatero, I., Kurppa, K. and Elenius, K., Laajala, T.D., Westermarck, J., 2023. Transcriptional landscape of DTP-DTEP transition reveals DUSP6 as a driver of HER2 inhibitor tolerance via Neuregulin/HER3 axis. bioRxiv, pp.2023-06.
[8] arikh AR, Leshchiner I, Elagina L, Goyal L, Levovitz C, Siravegna G, Livitz D, Rhrissorrakrai K, Martin EE, Van Seventer EE, Hanna M, Slowik K, Utro F, Pinto CJ, Wong A, Danysh BP, de la Cruz FF, Fetter IJ, Nadres B, Shahzade HA, Allen JN, Blaszkowsky LS, Clark JW, Giantonio B, Murphy JE, Nipp RD, Roeland E, Ryan DP, Weekes CD, Kwak EL, Faris JE, Wo JY, Aguet F, Dey-Guha I, Hazar-Rethinam M, Dias-Santagata D, Ting DT, Zhu AX, Hong TS, Golub TR, Iafrate AJ, Adalsteinsson VA, Bardelli A, Parida L, Juric D, Getz G, Corcoran RB. Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers. Nat Med. 2019 Sep;25(9):1415-1421. doi: 10.1038/s41591-019-0561-9. Epub 2019 Sep 9. Erratum in: Nat Med. 2019 Dec;25(12):1949. PMID: 31501609; PMCID: PMC6741444.
[9] Leshchiner, I., Livitz, D., Gainor, J.F., Rosebrock, D., Spiro, O., Martinez, A., Mroz, E., Lin, J.J., Stewart, C., Kim, J. and Elagina, L., Shaw, A.T., Getz, G., 2019. Comprehensive analysis of tumour initiation, spatial and temporal progression under multiple lines of treatment. biorxiv, p.508127.
[10] Bosc C, Saland E, Bousard A, Gadaud N, Sabatier M, Cognet G, Farge T, Boet E, Gotanègre M, Aroua N, Mouchel PL, Polley N, Larrue C, Kaphan E, Picard M, Sahal A, Jarrou L, Tosolini M, Rambow F, Cabon F, Nicot N, Poillet-Perez L, Wang Y, Su X, Fovez Q, Kluza J, Argüello RJ, Mazzotti C, Avet-Loiseau H, Vergez F, Tamburini J, Fournié JJ, Tiong IS, Wei AH, Kaoma T, Marine JC, Récher C, Stuani L, Joffre C, Sarry JE. Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia. Nat Cancer. 2021 Nov;2(11):1204-1223. doi: 10.1038/s43018-021-00264-y. Epub 2021 Nov 11. PMID: 35122057.
[11] Lechner S, Malgapo MIP, Grätz C, Steimbach RR, Baron A, Rüther P, Nadal S, Stumpf C, Loos C, Ku X, Prokofeva P, Lautenbacher L, Heimburg T, Würf V, Meng C, Wilhelm M, Sippl W, Kleigrewe K, Pauling JK, Kramer K, Miller AK, Pfaffl MW, Linder ME, Kuster B, Médard G. Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target. Nat Chem Biol. 2022 Aug;18(8):812-820. doi: 10.1038/s41589-022-01015-5. Epub 2022 Apr 28. Erratum in: Nat Chem Biol. 2022 Jul 15;: PMID: 35484434; PMCID: PMC9339481.
[12] Zecha J, Bayer FP, Wiechmann S, Woortman J, Berner N, Müller J, Schneider A, Kramer K, Abril-Gil M, Hopf T, Reichart L, Chen L, Hansen FM, Lechner S, Samaras P, Eckert S, Lautenbacher L, Reinecke M, Hamood F, Prokofeva P, Vornholz L, Falcomatà C, Dorsch M, Schröder A, Venhuizen A, Wilhelm S, Médard G, Stoehr G, Ruland J, Grüner BM, Saur D, Buchner M, Ruprecht B, Hahne H, The M, Wilhelm M, Kuster B. Decrypting drug actions and protein modifications by dose- and time-resolved proteomics. Science. 2023 Apr 7;380(6640):93-101. doi: 10.1126/science.ade3925. Epub 2023 Mar 16. PMID: 36926954; PMCID: PMC7615311.
