Exploration of Targeted Anti-tumor Therapy

Table 1. Characteristics of colorectal cancers with APC, RNF43, CTNNB1, or TCF7L2 alterations from the Cancer Genome Atlas (TCGA)

Characteristic	Entire cohort (n = 594)	Quadruple altered (n = 95)	APC only altered (n = 300)	Triple altered (n = 44)	Quadruple wild type (n = 95)	P
Age (mean ± SD)	66.1 ± 13.4	64.4 ± 13	66.2 ± 11.9	65.8 ± 16.5	65.7 ± 14.3	0.72
Age
≤ 65 years-old	260 (43.9)	48 (51.1)	134 (44.8)	18 (40.9)	40 (42.1)	0.56
> 65 years-old	332 (56.1)	46 (48.9)	165 (55.2)	26 (59.1)	55 (57.9)	0.56
NA	2	1	1	0	0	-
Sex
Male	312 (52.7)	47 (50)	164 (54.8)	23 (52.3)	43 (45.3)	0.41
Female	280 (47.3)	47 (50)	135 (45.2)	21 (47.7)	52 (54.7)	0.41
NA	2	1	1	0	0	-
Stage
I	104 (17.9)	13 (14.4)	59 (20.1)	6 (13.6)	17 (18.3)	I–II versus III–IV: 0.26
II	220 (37.9)	39 (43.3)	98 (33.5)	23 (52.3)	41 (44.1)
III	170 (29.3)	23 (25.6)	97 (33.1)	12 (27.3)	19 (20.4)
IV	86 (14.8)	15 (16.7)	39 (13.3)	3 (6.8)	16 (17.2)
NA	14	5	7	0	2	-
Location primary
Colon	436 (74.1)	70 (75.3)	209 (70.4)	41 (93.2)	71 (75.5)	0.01
Rectal	152 (25.9)	23 (24.7)	88 (29.6)	3 (6.8)	23 (24.5)	0.01
NA	6	2	3	0	1	-

Return to article view

Percentages are shown in parentheses. NA: not available; SD: standard deviation; APC: adenomatous polyposis coli. -: no data

Declarations

Author contributions

IAV: Conceptualization, Investigation, Writing—original draft, Writing—review & editing.

Conflicts of interest

The author declares that there have no conflicts of interest.

Ethical approval

The study was an analysis of previously published data and was exempt from approval by an Ethics Committee.

Consent to participate

The study was an analysis of previously published data and informed consent was not required or obtained.

Consent to publication

Not applicable.

Availability of data and materials

The datasets analyzed for this study can be found in the Cancer Genome Atlas [http://www.cancer.gov/ccg/]; Cancer Cell Line Encyclopedia [http://www.sites.broadintitute.org/ccle/]; Genomics of Drug Sensitivity in Cancer (GDSC) project [http://www.cancerrxgene.org]; project Achilles, Drive, Marcotte DEMETER2 [http://www.depmap.org/portal/achilles]; DepMap, Public 24Q2+Score, and Chronos projects [http://www.depmap.org].

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49. Erratum in: CA Cancer J Clin. 2024;74:203. [DOI] [PubMed]

Arnold M, Abnet CC, Neale RE, Vignat J, Giovannucci EL, McGlynn KA, et al. Global Burden of 5 Major Types of Gastrointestinal Cancer. Gastroenterology. 2020;159:335–49.e15. [DOI] [PubMed] [PMC]

Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, et al. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19:329–59. [DOI] [PubMed]

André T, Shiu K, Kim TW, Jensen BV, Jensen LH, Punt C, et al.; KEYNOTE-177 Investigators. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. N Engl J Med. 2020;383:2207–18. [DOI] [PubMed]

Kopetz S, Grothey A, Yaeger R, Cutsem EV, Desai J, Yoshino T, et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019;381:1632–43. [DOI] [PubMed]

Siena S, Bartolomeo MD, Raghav K, Masuishi T, Loupakis F, Kawakami H, et al.; DESTINY-CRC01 investigators. Trastuzumab deruxtecan (DS-8201) in patients with HER2-expressing metastatic colorectal cancer (DESTINY-CRC01): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2021;22:779–89. [DOI] [PubMed]

Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, et al. Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C. N Engl J Med. 2023;388:44–54. [DOI] [PubMed] [PMC]

Pathak PS, Chan G, Deming DA, Chee CE. State-of-the-Art Management of Colorectal Cancer: Treatment Advances and Innovation. Am Soc Clin Oncol Educ Book. 2024;44:e438466. [DOI] [PubMed]

Voutsadakis IA. KRAS mutated colorectal cancers with or without PIK3CA mutations: Clinical and molecular profiles inform current and future therapeutics. Crit Rev Oncol Hematol. 2023;186:103987. [DOI] [PubMed]

10.

Fasano M, Pirozzi M, Miceli CC, Cocule M, Caraglia M, Boccellino M, et al. TGF-β Modulated Pathways in Colorectal Cancer: New Potential Therapeutic Opportunities. Int J Mol Sci. 2024;25:7400. [DOI] [PubMed] [PMC]

11.

Fujita M, Demizu Y. Advances in the development of Wnt/β-catenin signaling inhibitors. [Epub ahead of print]. 2024 [cited 2024 Nov 02]. [DOI] [PubMed] [PMC]

12.

Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7. [DOI] [PubMed] [PMC]

13.

Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, et al. Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Rep. 2016;15:857–65. Erratum in: Cell Rep. 2016;17:1206. [DOI] [PubMed] [PMC]

14.

Voutsadakis IA. The ubiquitin-proteasome system in colorectal cancer. Biochim Biophys Acta. 2008;1782:800–8. [DOI] [PubMed]

15.

Hankey W, Frankel WL, Groden J. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: implications for therapeutic targeting. Cancer Metastasis Rev. 2018;37:159–72. [DOI] [PubMed] [PMC]

16.

Ellrott K, Bailey MH, Saksena G, Covington KR, Kandoth C, Stewart C, et al.; MC3 Working Group; Cancer Genome Atlas Research Network. Scalable Open Science Approach for Mutation Calling of Tumor Exomes Using Multiple Genomic Pipelines. Cell Syst. 2018;6:271–81.e7. [DOI] [PubMed] [PMC]

17.

Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12:R41. [DOI] [PubMed] [PMC]

18.

Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30:413–21. [DOI] [PubMed] [PMC]

19.

Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 2012;483:603–7. Erratum in: Nature. 2012;492:290. Erratum in: Nature. 2019;565:E5–6. [DOI] [PubMed] [PMC]

20.

Iorio F, Knijnenburg TA, Vis DJ, Bignell GR, Menden MP, Schubert M, et al. A Landscape of Pharmacogenomic Interactions in Cancer. Cell. 2016;166:740–54. [DOI] [PubMed] [PMC]

21.

Behan FM, Iorio F, Picco G, Gonçalves E, Beaver CM, Migliardi G, et al. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature. 2019;568:511–6. [DOI] [PubMed]

22.

Boehm JS, Garnett MJ, Adams DJ, Francies HE, Golub TR, Hahn WC, et al. Cancer research needs a better map. Nature. 2021;589:514–6. [DOI] [PubMed]

23.

van der Meer D, Barthorpe S, Yang W, Lightfoot H, Hall C, Gilbert J, et al. Cell Model Passports-a hub for clinical, genetic and functional datasets of preclinical cancer models. Nucleic Acids Res. 2019;47:D923–9. [DOI] [PubMed] [PMC]

24.

Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a Cancer Dependency Map. Cell. 2017;170:564–76.e16. [DOI] [PubMed] [PMC]

25.

Marcotte R, Sayad A, Brown KR, Sanchez-Garcia F, Reimand J, Haider M, et al. Functional Genomic Landscape of Human Breast Cancer Drivers, Vulnerabilities, and Resistance. Cell. 2016;164:293–309. [DOI] [PubMed] [PMC]

26.

Dwane L, Behan FM, Gonçalves E, Lightfoot H, Yang W, van der Meer D, et al. Project Score database: a resource for investigating cancer cell dependencies and prioritizing therapeutic targets. Nucleic Acids Res. 2021;49:D1365–72. [DOI] [PubMed] [PMC]

27.

Meyers RM, Bryan JG, McFarland JM, Weir BA, Sizemore AE, Xu H, et al. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet. 2017;49:1779–84. [DOI] [PubMed] [PMC]

28.

Dempster JM, Boyle I, Vazquez F, Root DE, Boehm JS, Hahn WC, et al. Chronos: a cell population dynamics model of CRISPR experiments that improves inference of gene fitness effects. Genome Biol. 2021;22:343. [DOI] [PubMed] [PMC]

29.

Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2:401–4. Erratum in: Cancer Discov. 2012;2:960. [DOI] [PubMed] [PMC]

30.

Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1. [DOI] [PubMed] [PMC]

31.

Baulies A, Angelis N, Li VSW. Hallmarks of intestinal stem cells. Development. 2020;147:dev182675. [DOI] [PubMed]

32.

Basak O, Beumer J, Wiebrands K, Seno H, Oudenaarden Av, Clevers H. Induced Quiescence of Lgr5+ Stem Cells in Intestinal Organoids Enables Differentiation of Hormone-Producing Enteroendocrine Cells. Cell Stem Cell. 2017;20:177–90.e4. [DOI] [PubMed]

33.

Zhang C, Jin Y, Marchetti M, Lewis MR, Hammouda OT, Edgar BA. EGFR signaling activates intestinal stem cells by promoting mitochondrial biogenesis and β-oxidation. Curr Biol. 2022;32:3704–19.e7. [DOI] [PubMed] [PMC]

34.

Voutsadakis IA. Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome system and Cox-2. J Cell Mol Med. 2007;11:252–85. [DOI] [PubMed] [PMC]

35.

Perochon J, Carroll LR, Cordero JB. Wnt Signalling in Intestinal Stem Cells: Lessons from Mice and Flies. Genes (Basel). 2018;9:138. [DOI] [PubMed] [PMC]

36.

Voutsadakis IA. Molecular Alterations and Putative Therapeutic Targeting of Planar Cell Polarity Proteins in Breast Cancer. J Clin Med. 2023;12:411. [DOI] [PubMed] [PMC]

37.

Tabernero J, Cutsem EV, Garralda E, Tai D, Braud FD, Geva R, et al. A Phase Ib/II Study of WNT974 + Encorafenib + Cetuximab in Patients With BRAF^V600E-Mutant KRAS Wild-Type Metastatic Colorectal Cancer. Oncologist. 2023;28:230–8. [DOI] [PubMed] [PMC]

38.

Lung H, Wentworth KL, Moody T, Zamarioli A, Ram A, Ganesh G, et al. Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone. JBMR Plus. 2024;8:ziae011. [DOI] [PubMed] [PMC]

39.

Kim MK. Novel insight into the function of tankyrase. Oncol Lett. 2018;16:6895–902. [DOI] [PubMed] [PMC]

40.

Klement K, Brückner M, Bernkopf DB. Phosphorylation of axin within biomolecular condensates counteracts its tankyrase-mediated degradation. J Cell Sci. 2023;136:jcs261214. [DOI] [PubMed] [PMC]

41.

Fearon ER. PARsing the phrase “all in for Axin” - Wnt pathway targets in cancer. Cancer Cell. 2009;16:366–8. [DOI] [PubMed]

42.

Huang SA, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, et al. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461:614–20. [DOI] [PubMed]

43.

Masuda M, Sawa M, Yamada T. Therapeutic targets in the Wnt signaling pathway: Feasibility of targeting TNIK in colorectal cancer. Pharmacol Ther. 2015;156:1–9. [DOI] [PubMed]

44.

Shitashige M, Satow R, Jigami T, Aoki K, Honda K, Shibata T, et al. Traf2- and Nck-interacting kinase is essential for Wnt signaling and colorectal cancer growth. Cancer Res. 2010;70:5024–33. [DOI] [PubMed]

45.

Yamamoto D, Oshima H, Wang D, Takeda H, Kita K, Lei X, et al. Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer. J Pathol. 2022;257:39–52. [DOI] [PubMed] [PMC]

46.

Stefanski CD, Prosperi JR. Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response. Int J Mol Sci. 2020;21:7844. [DOI] [PubMed] [PMC]

47.

Lessey LR, Robinson SC, Chaudhary R, Daniel JM. Adherens junction proteins on the move-From the membrane to the nucleus in intestinal diseases. Front Cell Dev Biol. 2022;10:998373. [DOI] [PubMed] [PMC]