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Identifying Novel Actionable Targets in Colon Cancer

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Identifying Novel Actionable Targets in Colon Cancer biomedicines Review Identifying Novel Actionable Targets in Colon Cancer Maria Grazia Cerrito and Emanuela Grassilli * Department of Medicine and Surgery, University of Milano-Bicocca, Via Cadore 48, 20900 Monza, Italy; [email protected] * Correspondence: [email protected] Abstract: Colorectal cancer is the fourth cause of death from cancer worldwide, mainly due to the high incidence of drug-resistance toward classic chemotherapeutic and newly targeted drugs. In the last decade or so, the development of novel high-throughput approaches, both genome-wide and chemical, allowed the identification of novel actionable targets and the development of the relative specific inhibitors to be used either to re-sensitize drug-resistant tumors (in combination with chemotherapy) or to be synthetic lethal for tumors with specific oncogenic mutations. Finally, high- throughput screening using FDA-approved libraries of “known” drugs uncovered new therapeutic applications of drugs (used alone or in combination) that have been in the clinic for decades for treating non-cancerous diseases (re-positioning or re-purposing approach). Thus, several novel actionable targets have been identified and some of them are already being tested in clinical trials, indicating that high-throughput approaches, especially those involving drug re-positioning, may lead in a near future to significant improvement of the therapy for colon cancer patients, especially in the context of a personalized approach, i.e., in defined subgroups of patients whose tumors carry certain mutations. Keywords: colon cancer; drug resistance; target therapy; high-throughput screen; si/sh-RNA screen; CRISPR/Cas9 knockout screen; drug re-purposing; drug re-positioning Citation: Cerrito, M.G.; Grassilli, E. Identifying Novel Actionable Targets in Colon Cancer. Biomedicines 2021, 9, 579. https://doi.org/10.3390/ 1. Introduction biomedicines9050579 1.1. Biology of Colorectal Cancer Colorectal cancer (CRC) formation begins with the transformation of a normal colorec- Academic Editor: Valeria Barresi tal epithelium to a benign adenoma. It then progresses through the stepwise accumulation of multiple genetic and epigenetic aberrations by three major pathways: chromosomal Received: 23 April 2021 Accepted: 14 May 2021 instability (CIN), microsatellite instability (MSI) and CpG island methylator (CIMP+) phe- Published: 20 May 2021 notype. These pathways are not mutually exclusive, with some tumors exhibiting features of multiple pathways; in all cases, the point of arrival is the carcinoma which subsequently Publisher’s Note: MDPI stays neutral progresses to an invasive and metastatic tumor [1] (Figure1). with regard to jurisdictional claims in Almost 85% of sporadic CRCs present CIN, which results from defects in chro- published maps and institutional affil- mosomal segregation, telomere stability and the DNA damage response, and leads to iations. gain/losses of chromosomal segments, chromosomal rearrangements and LOH of tumor suppressor genes, such as APC, TP53, DCC and SMAD family members (SMAD2 and SMAD4), eventually resulting in the dysregulation of several important signaling pathways (Figures2 and3). Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). Biomedicines 2021, 9, 579. https://doi.org/10.3390/biomedicines9050579 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 41 Biomedicines 2021, 9, 579 2 of 40 FigureFigure 1. Schematic 1. Schematic representation representation of ofCRC CRC progression progression along along the threethree different different pathways pathways according according to the to Fearonthe Fearon and and VogelsteinVogelstein model. model. CIN, CIN, chromosomal chromosomal instability; MSI, MSI, microsatellite microsatellite instability; instability; CIMP, CIMP, CpG island CpG methylator; island methylator; MMR, DNA MMR, DNA mismatchmismatch repair; repair; LOH, LOH, loss loss of heterozygosity. of heterozygosity. Independently Independentl of they pathway, of the pathway, a defect in a thedefect APC/beta-catenin in the APC/beta-catenin axis marks axis marksthe the onset onset of theof the transformation transformation process pr fromocess normal from normal epithelia epithelia to early adenoma. to early Aadenoma. defect along A defect the KRAS/BRAF along the pathwayKRAS/BRAF pathwayis required is required to progress to progress to intermediate to intermediate adenoma. adenoma. Loss or silencing Loss or of silencing different tumorof different suppressor tumor genes suppressor finally determines genes finally determinesthe progression the progression to late adenoma to late andadenom then toa and carcinoma. then to In carcinoma. the CIN pathway, In the the CIN transition pathway, to the the carcinoma transition stage to isthe marked carcinoma stage byis marked the inactivation by the inactivation of the tumor-suppressor of the tumor-suppressor gene TP53, whose gene product TP53, is whose pivotal produc in regulatingt is pivotal DNA repair,in regulating cell cycle DNA arrest, repair, cell cyclesenescence, arrest, senescence, apoptosis and apoptosis metabolism and in metabolism response to in a varietyresponse of stressto a variety signals. of Therefore,stress signals. its loss Therefore, contributes its toloss drug contrib- utes toresistance drug resistance and to the and propagation to the propagation of damaged DNAof damaged to daughter DN cells,A to increasingdaughter the cells, mutational increasi load.ng the TP53 mutational mutation orload. loss TP53 mutationof it hasor loss been of reported it has been in 50–75% reported of CRC in cases50–75% and of it isCRC associated cases and with it the is progressionassociated andwith outcome the progression of sporadic and CRC outcome [2,3]. of sporadic CRC [2,3]. Biomedicines 2021, 9, 579 3 of 40 Biomedicines 2021, 9, x FOR PEER REVIEW 3 of 41 Figure Figure2. WNT/beta-catenin 2. WNT/beta-catenin canonical canonical signaling signaling path pathwayway in CRC in CRC and and identified identified inhibitors. inhibitors. When When WNT WNT proteins proteins areare se- questeredsequestered by WNT by inhibitory WNT inhibitory factor-1 factor-1 (WIF-1), (WIF-1), the themember member of ofthe the frizzled frizzled (FZD (FZD)) familyfamily of of atypical atypical G protein-coupledG protein-coupled receptorsreceptors is inhibited is inhibited by a secreted by a secreted frizzled-related frizzled-related protein protein (SFRP) (SFRP) and and the the co-receptor co-receptor lipoproteinlipoprotein receptor-related receptor-related protein protein (LPR) 5(LPR) or 6 5is orbound 6 is bound to Dickkopf to Dickkopf (DKK); (DKK); WNT WNT signaling signaling is isth thereforeerefore off. off. As aa consequence,consequence, the the receptor receptor complex complex is not is not formedformed and the and destruction the destruction complex complex is isassembled assembled in in the the cytoplasm,cytoplasm, where where APC APC and and AXIN AXIN serve serve as a scaffold as a scaffold to recruit to CK1 recruit CK1 andand GSK3B, GSK3B, both both of which phosphorylate phosphorylate beta-catenin, beta-catenin, thus th targetingus targeting it for BTRC-mediatedit for BTRC-med ubiquitinationiated ubiquitination and subsequent and sub- sequent proteasome-mediated degradation. In the nucleus, TCF/LEF transcription factor sits on the promoter of WNT- proteasome-mediated degradation. In the nucleus, TCF/LEF transcription factor sits on the promoter of WNT-regulated regulated genes where, via binding a member of the Groucho/TLE family of transcription repressors or CtBP, it recruits genes where, via binding a member of the Groucho/TLE family of transcription repressors or CtBP, it recruits HDAC to HDAC to repress transcription of the downstream genes. The signaling starts when WNT is freed and can bind a member repress transcription of the downstream genes. The signaling starts when WNT is freed and can bind a member of FZD of FZD family LPR5/6, thus forming the receptor complex which, via the binding of the adaptor protein Disheveled (DVL), family LPR5/6, thus forming the receptor complex which, via the binding of the adaptor protein Disheveled (DVL), recruits recruits to the membrane the destruction complex, disrupting it. Tankyrases (TNKSs,) by poly-ADP-ribosylating AXIN, to the membrane the destruction complex, disrupting it. Tankyrases (TNKSs,) by poly-ADP-ribosylating AXIN, prime it for prime it for ubiquitination and subsequent proteasome-mediated degradation. Alternatively, AXIN can sequester GSK3B ubiquitination and subsequent proteasome-mediated degradation. Alternatively, AXIN can sequester GSK3B away from away from the complex; in both ways beta-catenin is released from the destruction complex and translocates to the nu- the complex; in both ways beta-catenin is released from the destruction complex and translocates to the nucleus, where cleus, where it displaces transcription repressors and complexes with TCF/LEF to recruit several transcriptional coactiva- it displaces transcription repressors and complexes with TCF/LEF to recruit several transcriptional coactivators (Pygo, tors (Pygo, BCL9) and histone modifiers (such as TRRAP, PAF1, BRG1, etc.) in order to promote the transcription of the BCL9) and histone modifiers (such as TRRAP, PAF1, BRG1, etc.) in order to promote the transcription
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