Novel Wnt signaling and other pathway inhibitors in the colorectal cancer genomic landscape era

Abstract

Future OncologyVol. 8, No. 11 EditorialFree AccessNovel Wnt signaling and other pathway inhibitors in the colorectal cancer genomic landscape eraDimitrios H Roukos, Demosthenes E Ziogas, Costas Papaloukas & George BaltogiannisDimitrios H Roukos* Author for correspondenceCentre for BioSystems & Genomic Network Medicine – CBS.GenNetMed, Ioannina University, Ioannina, Greece. Search for more papers by this authorEmail the corresponding author at droukos@uoi.gr, Demosthenes E ZiogasCentre for BioSystems & Genomic Network Medicine – CBS.GenNetMed, Ioannina University, Ioannina, GreeceDepartment of Surgery, Ioannina University Hospital, Ioannina, GreeceSearch for more papers by this author, Costas PapaloukasCentre for BioSystems & Genomic Network Medicine – CBS.GenNetMed, Ioannina University, Ioannina, GreeceDepartment of Biological Applications & Technology, University of Ioannina, GR 45110 Ioannina, GreeceSearch for more papers by this author & George BaltogiannisDepartment of Surgery, Ioannina University Hospital, Ioannina, GreeceSearch for more papers by this authorPublished Online:14 Nov 2012https://doi.org/10.2217/fon.12.140AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit Keywords: biomarkersCRC drugsEGFRgenomic landscaperesistanceWntIn contrast with previous studies with retrospective analysis of KRAS status [1,2] and with recent approval by the US FDA [101] suggesting survival benefit by adding cetuximab to chemotherapy in wild-type metastatic colorectal cancer (CRC), several more recent Phase III randomized controlled trials have shown no survival benefit when cetuximab was added to chemotherapy in patients with wild-type (wt)-KRAS CRC [3–5]. It is no surprise that current guidelines do not recommend anti-EGF receptor antibody drugs as first-line treatment of CRC even among wild-type tumors. High-throughput (HT) platforms including sequencing technologies and modern array-based techniques are currently increasingly used. By providing a multiscale set of omics data and a comprehensive view of the cancer genome landscape they promise the discovery of clinically robust biomarkers and therapeutic targets [6–8]. To understand and overcome resistance to EGF receptor (EGFR)-targeted antibodies in CRC, research has been shifted toward identification of new drugs such as MEK inhibitors [9,10] or inhibitors of Wnt signaling pathway targeting the BCL9–β-catenin interaction [11]. These perspectives, together with current reports on the integrative genomic landscape of CRC, are discussed here [12,13]. The aim is to see whether we are close to genome architecture-based personalized treatment of CRC. Emphasis is given in research efforts to achieve targeted drugs with longer and more durable antitumor effect than the currently used targeted drugs with limited and short efficacy for improving clinical outcomes.Current standard treatmentNonspecific multimodal therapy still remains the standard approach in the treatment of CRC. For resectable stage II and III tumors surgical resection and adjuvant chemotherapy is the standard approach for colon cancer, while in rectal cancer the addition of radiotherapy in locally advanced or nonresectable tumors is recommended. In metastatic stage IV tumors with completely resectable (R0) liver or lung metastases in the primary diagnosis or after neoadjuvant treatment surgery, systemic chemotherapy is recommended by the National Comprehensive Cancer Network, similarly to the treatment of stage III disease [102].Targeted therapy represents a new systemic anticancer therapy. Drugs targeting specific defected genes and the signaling pathways in which they are involved present a major hope for improving oncological outcomes. This specific tumor-guided therapy rapidly became very popular for a variety of cancer types because it was thought it enabled high antitumor efficacy with a low side effect profile. However, more recent appropriately designed and conducted Phase III randomized controlled trials substantially limit expectations.Generally, signal transduction inhibitors enable a transitory and nondurable anticancer activity [14] in selected subgroups of patients with specific genetic alterations [15]. Many approved targeted drugs provide a modest timely limited efficacy only, with the exceptions of trastuzumab, imatinib and vemurafenib. These drugs, in the defected genes-based selection of patients with breast cancer, chronic myeloid leukemia and melanoma, respectively, provide a true overall survival benefit [16]. In summary, it is now clear that one drug does not fit all patients stratified by conventional clinicopathologic features and single-gene testing. Thus, efforts towards personalized health are predominantly focused on how to identify genomic landscape-based tools for tailoring the best drugs combination in individual patients [17,18].KRAS, BRAF & anti-EGF receptor antibodiesAlthough cetuximab (Erbitux®) was approved by the US FDA in 2004 for the treatment of patients with EGFR-expressing metastatic CRC (mCRC), in July 2012 this approval changed to use in combination with FOLFIRI (irinotecan, 5-fluorouracil and leucovorin) for first-line treatment of patients with KRAS mutation-negative (wt-KRAS) mCRC only. This decision was based on the CRYSTAL trial update that suggested overall survival benefit and progression-free survival benefit in wt-KRAS mCRC [1] and the supporting OPUS trial [2]. However, there has been criticism on retrospective analyses of KRAS status and the inconsistent findings of these studies.To clarify the question of efficacy and assess the effect of EGFR-targeted cetuximab in survival of patients with CRC, three new randomized controlled trials have recently been reported. In all these studies there was a central determination of careful re-evaluation of KRAS status in tumor samples and the number of patients even among the wt-KRAS subgroup had the power to detect appropriate significant differences. In the metastatic setting, in both the MRC COIN trial [3] and the NORDIC-VII study [4], the addition of cetuximab to chemotherapy did not significantly improve overall survival or progression-free survival in the wt-KRAS mCRC subset of patients. In the MRC COIN study, cetuximab increased response rate from 57 to 64% (p = 0.049). Similarly, in the first published study on the adjuvant setting, the addition of cetuximab in 2686 randomized patients with resected stage III wt-KRAS colon cancer did not improve disease-free survival [5]. Based on this latest evidence [3–5], the National Comprehensive Cancer Network, with effect in 2012, does not recommend cetuximab in the adjuvant treatment of stage III colon cancer. In the metastatic setting the recommendations have also changed; cetuximab or panitumumab are not recommended as first-line therapy but, given a potential response to EGFR-targeted antibodies in some patients, these drugs could be considered in disease progression under standard chemotherapy [102]. To overcome secondary and primary resistance to cetuximab or panitumumab, current research is exploring molecular mechanisms underlying tumor unresponsiveness by studying the EGFR and Wnt pathway using HT sequencing to provide comprehensive omics analysis of CRC.EGFR, RAS & MEK pathwaysActivation of the EGFR pathway, which controls cell survival, proliferation, growth and apoptosis, deregulates signal transduction from the cell surface to the nucleus through phosphorylation of intracellular RAS–RAF–MEK or PI3K–AKT–mTOR pathways, causing cancer. Mutations in KRAS CRC cells can provide them with the capacity to escape the EGFR blockade by cetuximab, explaining tumor resistance to this therapy. However, how can secondary resistance to cetuximab or panitumumab treatment in wt-KRAS CRC be explained? Two recent papers in Nature support that emergent driver KRAS mutations at low levels and thus undetectable in primary mutation testing, or secondary acquired mutations after wt-KRAS CRC diagnosis, are the main causes of resistance to EGFR blockade with cetuximab or panitumumab in wt-KRAS CRC patients [9,10]. The authors propose KRAS mutant clones measurement in the blood circulation as a predictive marker of resistance and the development of early treatment of these patients with addition of a MEK inhibitor to anti-EGFR antibody for overcoming resistance [9].The hypothesis and findings of these two reports for emergent mutations provide a logical explanation of anti-EGFR drug resistance in wt-KRAS CRC. However, in the study by Diaz et al., in 62% of cases there were no emergent mutations [10]. Research should be guided by high-level evidence from Phase III trials that reveals a small response rate of 7% only with cetuximab in wt-KRAS CRC [3], without a survival benefit [3–5]. Thus, in the research arena, interest is now increasingly being focused on the discovery of druggable targets exploring the Wnt signaling pathway and other genome landscape-based targets.Wnt signalingThe Wnt signaling pathway controls cell behavior through a signal transduction network involving interacting genes, proteins and molecules. This Wnt signaling is essential for embryonic development, stem cells and tissue regeneration. Deregulation of this pathway, mostly through mutations of genes involved in the pathway, is associated with a variety of cancer types. Particularly for CRC, the Cancer Genome Atlas project found that the Wnt signaling pathway was altered in 93% of all tumors [13].It is no surprise therefore that substantial effort is focused on how to develop Wnt signaling inhibitors. However, development of targeted drugs to disrupt Wnt signaling dysfunction has been challenging owing to the large protein interaction surfaces and the possibility of high adverse effects when targeting a whole network, and also by disrupting vital pathways and functions.One of the proteins involved in the Wnt pathway is BCL9, which is overexpressed in CRC and, by forming a BCL9–β-catenin complex, results in overexpression of these proteins encoded by these genes. By targeting this BCL9–β-catenin interaction, Takada and colleagues have reported that this disruption can inhibit Wnt signaling in Wnt-dependent CRC [11].The genomic landscapeHT genome-wide mapping technologies have rapidly evolved, providing the current capacity for performing deep-genome sequencing and integrative omics analysis in clinical samples at acceptable costs. Linking genome landscape-based discoveries generated from analysis of patients’ tumor samples and their corresponding clinical data on disease prognosis, treatment response, recurrence and survival can lead to the development of novel biomarkers and drugs targeted identification.Recently, two studies performing genome sequencing and integrative omics analysis in 70 and 276 samples, respectively, from CRC patients have been reported [12,13]. Using a variety of HT sequencing and array-based platforms, these two studies provide important genomic results with potential clinical implications.The Cancer Genome Atlas project has performed a comprehensive integrative analysis in 224 colorectal tumors and normal pairs [13]. The genomic landscape-based information obtained in a substantial number of CRC samples has allowed the generation of important data. In total, 24 mutated genes were found, including the well known APC, TP53, SMAD4, PIK3CA and KRAS genes and, in addition, mutations were also found in the ARID1A, SOX9 and FAM123B genes. A finding with potential clinical utility is the copy-number alterations and amplifications of ERBB2. Given the availability of the anti-ERBB2 antibody trastuzumab, with clinical success in ERBB2-positive breast cancer and gastric cancer [16], this raises promise for testing it in ERBB2-positive CRC.The Wnt signaling pathway was found to be deregulated in 93% of CRC and had a crucial role in the disease, supporting the research that is underway for therapeutic implications of Wnt signaling inhibitors and small-molecule β-catenin inhibitors in CRC. In addition, the MYC gene plays a crucial role in CRC.Conclusion & future perspectiveThe recent evidence of modest efficacy of the anti-EGFR antibodies in the treatment of CRC with no overall survival benefit for the patients with wt-KRAS status has shifted research toward the development of Wnt signaling pathway inhibitors in Wnt-dependent CRC, as well as drugs inhibiting other deregulated pathways involved in CRC. Some promising data have been reported. However, we should await completed data from studies because in the Wnt pathways the signal is transduced through a complex molecule interactions network that is only partially understood and considered in the drugs development pipeline. More recently, hope for developing more effective and robust for-the-clinic markers and drugs is emerging from comprehensive genome analysis studies. Using a combination of HT sequencing and array platforms in clinical samples from CRC patients, new genomic discoveries have arisen [12.13]. However, how to translate this genomic landscape information into the clinic has not been identified. For example, understanding and predicting regulatory networks of expression of multiple genes and cell signaling networks is essential for clinical applications, but it has still proven to be a hard task despite advances in translational research [17–19]. Assessment of signaling pathways in individual patients’ samples is essential in personalized systems, pharmacology and medical decisions, but is still an unresolved problem despite advances in pathway analysis [20].Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.References1 Van Cutsem E, Köhne CH, Láng I et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J. Clin. Oncol.29(15),2011–2019 (2011).Crossref, Medline, CAS, Google Scholar2 Bokemeyer C, Bondarenko I, Makhson A et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J. Clin. Oncol.27(5),663–671 (2009).Crossref, Medline, CAS, Google Scholar3 Maughan TS, Adams RA, Smith CG et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised Phase 3 MRC COIN trial. Lancet377(9783),2103–2114 (2011).Crossref, Medline, CAS, Google Scholar4 Tveit KM, Guren T, Glimelius B et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study. J. Clin. Oncol.30(15),1755–1762 (2012).Crossref, Medline, CAS, Google Scholar5 Alberts SR, Sargent DJ, Nair S et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA307(13),1383–1393 (2012).Crossref, Medline, CAS, Google Scholar6 Roukos DH. Next-generation sequencing and epigenome technologies: potential medical applications. Expert Rev. Med. Devices7(6),723–726 (2010).Crossref, Medline, CAS, Google Scholar7 Chin L, Andersen JN, Futreal PA. Cancer genomics: from discovery science to personalized medicine. Nat. Med.17,297–303 (2011).Crossref, Medline, CAS, Google Scholar8 Roukos DH. Next-generation, genome sequencing-based biomarkers: concerns and challenges for medical practice. Biomark. Med.4(4),583–586 (2010).Link, Google Scholar9 Misale S, Yaeger R, Hobor S et al. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer. Nature486(7404),532–536 (2012).Crossref, Medline, CAS, Google Scholar10 Diaz LA Jr, Williams RT, Wu J, Kinde I et al. The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers. Nature486(7404),537–540 (2012).Crossref, Medline, CAS, Google Scholar11 Takada K, Zhu D, Bird GH et al. Targeted disruption of the BCL9/β-Catenin complex inhibits oncogenic Wnt signaling. Sci. Transl. Med.4(148),148ra117 (2012).Crossref, Medline, Google Scholar12 Seshagiri S, Stawiski EW, Durinck S et al. Recurrent R-spondin fusions in colon cancer. Nature488(7413),660–664 (2012).Crossref, Medline, CAS, Google Scholar13 Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature487(7407),330–337 (2012).Crossref, Medline, CAS, Google Scholar14 Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell144(5),646–674 (2011).Crossref, Medline, CAS, Google Scholar15 Roukos DH. Complete genome sequencing and network modeling to overcome trastuzumab resistance. Pharmacogenomics11(8),1039–1043 (2010).Link, CAS, Google Scholar16 Roukos DH. Trastuzumab and beyond: sequencing cancer genomes and predicting molecular networks. Pharmacogenomics J.11(2),81–92 (2011).Crossref, Medline, CAS, Google Scholar17 Califano A, Butte AJ, Friend S, Ideker T, Schadt E. Leveraging models of cell regulation and GWAS data in integrative network-based association studies. Nat. Genet.44(8),841–847 (2012).Crossref, Medline, CAS, Google Scholar18 Ideker T, Krogan NJ. Differential network biology. Mol. Syst. Biol.8,565 (2012).Crossref, Medline, Google Scholar19 Camacho DF, Pienta KJ. Disrupting the networks of cancer. Clin. Cancer Res.18(10),2801–2808 (2012).Crossref, Medline, CAS, Google Scholar20 Khatri P, Sirota M, Butte AJ. Ten years of pathway analysis: current approaches and outstanding challenges. PLoS Comput. Biol.8(2),e1002375 (2012).Crossref, Medline, CAS, Google Scholar101 US FDA: Cetuximab in combination with Folfiri/Therascreen. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm310933.htmGoogle Scholar102 NCCN Guidelines. www.nccn.org/professionals/physician_gls/f_guidelines.asp#colonGoogle ScholarFiguresReferencesRelatedDetailsCited ByResearch on Mechanism of Nanometer Colloidal Particles of Prostate Specific Membrane Aptamer A10 (PSMA-a10)/TGX221 in Restraining the Transplantation Tumor of Rats with Prostate Cancer (PCa)Journal of Biomaterials and Tissue Engineering, Vol. 12, No. 6 Vol. 8, No. 11 eToC Sign up Follow us on social media for the latest updates Metrics History Published online 14 November 2012 Published in print November 2012 Information© Future Medicine LtdKeywordsbiomarkersCRC drugsEGFRgenomic landscaperesistanceWntFinancial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download