Oncogene, Journal Year: 2021, Volume and Issue: 40(28), P. 4625 - 4651
Published: June 18, 2021
Language: Английский
Annals of Oncology, Journal Year: 2021, Volume and Issue: 32(9), P. 1101 - 1110
Published: June 2, 2021
•Better understanding of RAS signaling has led to the development promising directly blocking compounds in KRAS-mutant tumors.•New drug candidates take advantage increased knowledge KRAS mutation complex and relevant protein structures.•Increasing evidence continues demonstrate genomic heterogeneity KRAS-mutated NSCLC.•Current efforts include overcoming resistance after treatment with KRASG12C inhibitors. Rat sarcoma (RAS) is most frequently mutated oncogene human cancer, Kirsten rat (KRAS) being commonly isoform. Overall, accounts for 85% mutations observed cancers present 35% lung adenocarcinomas (LUADs). While use targeted therapies immune checkpoint inhibitors (CPIs) drastically changed landscape advanced non-small-cell cancer (NSCLC) recent years, historic attempts target (both direct indirect approaches) have had little success, no KRAS-specific been approved date patients this molecular subset NSCLC. With discovery by Ostrem, Shokat, colleagues switch II pocket on surface active inactive forms KRAS, we now an improved interactions involved family proteins which a number inhibitors, such as sotorasib adagrasib. In previously treated KRASG12C-mutant NSCLC, clinical activity shown both adagrasib monotherapy; these data suggest new options are horizon. stage set era KRASG12C-mutated many questions remain be answered order further elucidate mechanisms resistance, how best combination strategies, if will suitable earlier lines therapy advanced/metastatic cancer,1Soh J. Okumura N. Lockwood W.W. et al.Oncogene mutations, copy gains mutant allele specific imbalance (MASI) occur together tumor cells.PLoS One. 2009; 4: e7464Crossref PubMed Scopus (193) Google Scholar,2Bos J.L. Ras Oncogenes cancer: review.Cancer Res. 1989; 49: 4682-4689PubMed Scholar isoform3Prior I.A. Lewis P.D. Mattos C. A comprehensive survey cancer.Cancer 2012; 72: 2457-2467Crossref (1378) key clonal oncogenic driver. cancers.4Simanshu D.K. Nissley D.V. McCormick F. their regulators disease.Cell. 2017; 170: 17-33Abstract Full Text PDF (1024) The three types highest rate pancreatic (88%), colorectal (45%-50%), (31%-35%).5Prior Hood F.E. Hartley frequency 2020; 80: 2969-2974Crossref (393) Despite decades preclinical research aimed at identifying RAS, there specifically inhibiting or its downstream signaling. better proteins, however, that block NSCLC exploration approaches inhibit KRAS. These investigated monotherapies also other therapies, potential represent important advance article, discuss biology history targeting provide update emerging therapies. encodes membrane-bound guanosine triphosphatase (GTPase), when bound diphosphate (GDP) triphosphate (GTP).6Hallin Engstrom L.D. Hargis L. al.The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility mouse models patients.Cancer Discov. 10: 54-71Crossref (682) cycling GTP-bound state promoted guanine nucleotide exchange factor (GEF), son sevenless isoform 1 (SOS1) protein.7Vigil D. Cherfils Rossman K.L. Der C.J. superfamily GEFs GAPs: validated tractable targets therapy?.Nat Rev Cancer. 2010; 842-857Crossref (603) Scholar,8Hillig R.C. Sautier B. Schroeder al.Discovery potent SOS1 activation via disruption RAS-SOS1 interaction.Proc Natl Acad Sci U S A. 2019; 116: 2551-2560Crossref (218) This form acts like cellular that, turned extracellular stimuli, can activate pathways responsible fundamental cell processes9Malumbres M. Barbacid oncogenes: first 30 years.Nat 2003; 3: 459-465Crossref (1478) (Figure 1). Key effector mitogen-activated kinase (MAPK), phosphatidylinositol-3-kinase (PI3K), Ras-like (Ral) GEF (RalGEF); all effectors proliferation, cycle regulation, metabolic changes, survival, differentiation.10Stokoe Macdonald S.G. Cadwallader K. Symons Hancock J.F. Activation Raf result recruitment plasma membrane.Science. 1994; 264: 1463-1467Crossref (903) cycles between GTP- GDP-bound states resynthesis half-life ∼24 h.11Shukla S. Allam U.S. Ahsan al.KRAS stability regulated through SMURF2: UBCH5 complex-mediated beta-TrCP1 degradation.Neoplasia. 2014; 16: 115-128Crossref (69) Scholar,12Canon Rex Saiki A.Y. AMG 510 drives anti-tumour immunity.Nature. 575: 217-223Crossref (1139) dysregulated lead growth, playing role controlling cells microenvironment, ultimately affects response.13Carvalho Machado A.L. Martins Seruca R. Velho Targeting microenvironment: unexplored strategy tumors.Cancers (Basel). 11: 2010Crossref (31) Mutant associated decreased major histocompatibility class I (MHC I) expression, upregulation programmed death–ligand (PD-L1), promotion immunosuppressive population microenvironment (TME)13Carvalho recruitment, accumulation, maintenance myeloid-derived suppressor (MDSCs) TME.14Liao W. Overman M.J. Boutin A.T. al.KRAS-IRF2 axis suppression Cell. 35: 559-572.e7Abstract (306) Preclinical studies conducted adenocarcinoma (LUAD), pancreatic, alterations early carcinogenesis process promote invasion, migration.15Johnson Mercer Greenbaum al.Somatic K-ras causes onset mice.Nature. 2001; 410: 1111-1116Crossref (978) Point common dysregulation gene leads constitutively state, thereby triggering pathways.16Bourne H.R. Sanders D.A. GTPase superfamily: conserved diverse functions.Nature. 1990; 348: 125-132Crossref (2068) Scholar, 17Bourne structure mechanism.Nature. 1991; 349: 117-127Crossref (2952) 18Scheffzek Ahmadian M.R. Kabsch Ras-RasGAP complex: structural basis loss mutants.Science. 1997; 277: 333-338Crossref (1223) Smoking strongly cancer. more LUADs (20%-40%) less (∼5%) squamous NSCLC.19Martin P. Leighl N.B. Tsao M.-S. Shepherd F.A. prognostic predictive markers non-small cancer.J Thorac Oncol. 2013; 8: 530-542Abstract (98) Such cigarette smokers versus nonsmokers (30% 11%) Western Asian populations (26% 11%).20Adderley H. Blackhall F.H. Lindsay C.R. converging small molecules inhibition.EBioMedicine. 41: 711-716Abstract (126) up 30% NSCLC21Skoulidis Heymach J.V. Co-occurring therapy.Nat 19: 495-509Crossref (490) primarily (>95%) codons 12 13. large study found codon variants were from amino acid glycine (Gly) cysteine (Cys) (or G12C variants), accounted 39% followed Gly valine (Val) G12V (21%) G aspartic (Asp) G12D (17%).22Dogan Shen Ang D.C. al.Molecular epidemiology EGFR 3,026 adenocarcinomas: higher women smoking-related cancers.Clin Cancer 18: 6169-6177Crossref (472) Compared (P = 0.007).22Dogan addition, distribution differs smoking status. Smoking-associated (41% former [those who quit year before diagnosis] current still quite <1 diagnosis]) KRASG12V transversion DNA, involving changes (G) thymine (T) (Gua) cytosine (Cyt). On hand, among never-smokers (<100 lifetime cigarettes), was KRASG12D (56%), transition Gua adenine (Ade).22Dogan Data value conflicting. Some reports poor prognosis, while wild-type (WT) similar outcomes.23Rodenhuis van de Wetering M.L. Mooi W.J. Evers Zandwijk Bos Mutational oncogene. possible pathogenetic lung.N Engl J Med. 1987; 317: 929-935Crossref (495) 24Mascaux Iannino Martin survival systematic review literature meta-analysis.Br 2005; 92: 131-139Crossref (526) 25Villaruz L.C. Socinski M.A. Cunningham D.E. substitutions adenocarcinoma.Cancer. 119: 2268-2274Crossref (46) 26Goulding R.E. Chenoweth Carter G.C. meta-analysis.Cancer Treat Res Commun. 24: 100200Crossref (26) Although great progress discovering developing subsets LUAD made, currently drugs any mutation, occurs about one-third (see Figure 2).21Skoulidis subject extensive nearly 40 years. included itself well post-translational modifications, membrane localization, protein-protein interactions, pathways. Most not proved successful studies27Christensen J.G. Olson Briere T. Wiel Bergo M.O. Kras G12C-mutant mutation-specific inhibitor.J Intern 288: 183-191Crossref (56) Table 1), because, Shokat demonstrated, relatively shallow, smooth surface, exception GTP/GDP-binding pocket.6Hallin Scholar,28Jarvis L.M. Have hunters finally cracked KRas?.Chem Eng News. 2016; 94: 28-33Google Scholar,29Ostrem J.M.L. K.M. Direct small-molecule KRAS: insights mechanism-based design.Nat Drug 15: 771-785Crossref (383) ScholarTable 1Historical NSCLCTarget/pathwayDrug/assetRAF-MEK-ERKSalirasib, trametinib, sorafenibFarnesyl transferaseTipifarnib, ionafarnib, salirasibNF-κBBortezomibRhoA-FAKDefactinibPI3K-AKT-mTORRidaforolimus, sorafenib, copanlisibHSP90 MEKAUY-922, selumetinibMETPimasertib, ganetespib, onartuzumabHDAC inhibitionBelinastatDNA alkylationKR-12PDEδDeltasonamide 2GeranylgeranyltransferaseGGTI-2418KRAS siRNASGS6 siRNA, KRAS-siRNA NPKRAS (vaccine)mRNA-5671SOS1BI 1701963KRAS degradationPTD-RBD-VIFRAS-mimeticRigosertibGlutaminaseCB-839BCL2 MEK (synthetic lethality)Navitoclax, trametinibTBK1 lethality)Momelotinib, trametinibCDK4 lethality)Palbociclib, PD-0325901, abemaciclibSHP2 MEKSHP099, AZD6244AKT, B; BCL-2, B-cell lymphoma 2; CDK4, cyclin-dependent 4; ERK, receptor kinase; FAK, focal adhesion HDAC, histone deacetylase; Hsp90, heat shock 90; sarcoma; MEK, MET, mesenchymal-epithelial transition; mTOR: mammalian rapamycin; NF-kB: nuclear factor-kappa cancer; PDEδ, phosphodiesterase-δ; PI3K, phosphoinositide 3-kinase; RAF, rapidly accelerated fibrosarcoma; RhoA, homolog member A; RTK, tyrosine SHP2, Src homology interfering ribonucleic acid; SOS1, 1; TBK1, TANK-binding 1. Open table tab AKT, Until 5 years ago, seen highly challenging due complexity biochemistry,30Tomasini Walia Labbe Jao pathway cancer.Oncologist. 21: 1450-1460Crossref (91) high affinity GTP KRAS,31Gysin Salt Young Therapeutic strategies ras proteins.Genes 2011; 2: 359-372Crossref (264) limited binding sites.32Spoerner Herrmann Vetter I.R. Kalbitzer Wittinghofer Dynamic properties region importance effectors.Proc 98: 4944-4949Crossref (254) Recent advances computational modeling33Buhrman G. O'Connor Zerbe al.Analysis site hot spots GTPase.J Mol Biol. 413: 773-789Crossref (120) crystallography bind conformations.34Ostrem J.M. Peters U. Sos Wells J.A. K-Ras(G12C) allosterically control interactions.Nature. 503: 548-551Crossref (1469) early-stage needed substantially improved, them work effectively druggable target, they lacked potency some specificity RAS.35Shima Matsumoto Yoshikawa Y. Kawamura Isa Kataoka Current status inhibitors.J Biochem. 2015; 158: 91-99Crossref (25) Numerous indirectly explored well, including inhibition farnesylation required normal physiologic function transforming capacity mutants. Over last several decades, farnesyl transferase (FTIs) developed anticancer agents disrupt RAS. FTIs (e.g., tipifarnib salirasib) undergone investigation but efficacy NSCLC.36Adjei A.A. Mauer Bruzek al.Phase R115777 Clin 1760-1766Crossref (186) Scholar,37Riely G.J. Johnson Medina al.A phase trial salirasib mutations.J 6: 1435-1437Abstract (117) Mechanisms combat oncogenesis, alternative prenylation geranylgeranyl transferases, failure studies.38Heymach D.H. Khuri F.R. sensitive relapse small-cell cancer.Ann 2004; 1187-1193Abstract (96) Small inhibited fibrosarcoma (RAF) association reduced phosphorylation molecules, (MEK) (ERK).35Shima Scholar,39Shima Ye al.In silico display antitumor Ras-effector 110: 8182-8187Crossref (242) hypothesized inhibition, monotherapy trials modest. Selumetinib, allosteric, selective MEK1/2, demonstrated cancers.40Garon E.B. Finn R.S. Hosmer al.Identification vitro response selumetinib (AZD6244; ARRY-142886) breast lines.Mol Ther. 9: 1985-1994Crossref randomized 87 pretreated compared + docetaxel placebo, differences overall (OS) statistically significant (9.4 5.2 months; P 0.21). Differences measures did reach statistical significance: objective (ORR) selumetinib/docetaxel group 37% 0% docetaxel/placebo < 0.0001) progression-free (PFS) 5.3 2.1 months 0.014).41Janne P.A. Shaw Pereira J.R. al.Selumetinib plus randomized, multicentre, placebo-controlled, 2 study.Lancet 14: 38-47Abstract (570) another study, receive placebo second-line therapy. failed show improvement PFS (HR, 0.93)].42Janne den Heuvel M.M. Barlesi docetoxel alone SELECT-1 trial.JAMA. 1844-1853Crossref xenografts additional either p53 (TP53) 2A (CDKN2A; INK4A/ARF) loci (FAK) inhibition.43Gerber Camidge D.R. Morgensztern defactinib (VS-6063) previouslly cancer.Lung 139: 60-67Abstract (78) FAK heavily modest (median PFS, 45 days) TP53 CDKN2A status.43Gerber Seminal paved way generation KRASG12C. Their crystal GDP revealed beneath region, apparent previous RAS; allowed KRAS.34Ostrem since synthesized rely covalent (C). Sotorasib (AMG510) irreversibly selectively binds within locking it state. Pharmacokinetic (PK) analyses ∼5.5 h.44Govindan Phase 510, novel inhibitor, solid tumors mutation.in: Poster presented European Society Medical Oncology Congress. 2019Google evaluated I/II (CodeBreak 100: NCT03600883; 2) treated, locally metastatic malignancies harboring primary endpoint ORR. At 960-mg once daily dose continued until disease progression selected (N 124), ORR 37.1% (DCR) 80.6% 3). median duration 10.0 months, time 1.4 6.8 sotorasib. Grade 3 4 (This based standing staging criteria NSCLC) treatment-related adverse events (TRAEs) occurred 19.8% 126).45Hong D.S. Fakih M.G. Strickler J.H. al.KRAS(G12C) tumors.N 383: 1207-1217Crossref (852) Scholar,46Li L.T. CodeBreaK registrational p.G12C non cancer.in: Abstract 2020 Virtual World Conference Lung 2021Google TRAEs occurring >5% gastrointestinal toxicities diarrhea (4% grade 3), nausea, vomiting, hepatotoxicities alanine aminotransferase (ALT) increase (6.3% 3) aspartate (AST) (5.6% discontinuation 7.1% modification 22.2% patients. granted breakthrough designation Food Administration (FDA) application (NDA) filed December 2020. Furthermore, global III trial, CodeBreak 200 (NCT04303780), comparing ongoing.Table 2KRAS-targeting NSCLCTargetManufacturerAgentStatusClinicalTrials.gov identifierKRASG12CMirati Therapeutics, Inc.AdagrasibPhase I/IIPhase IIPhase IIINCT03785249NCT04330664NCT04613596NCT04685135KRASG12CAmgenSotorasibPhase IbPhase IIINCT04185883NCT03600883NCT04303780KRASG12CInventisBioD-1553Phase I/IINCT04585035KRASG12CGenentechGDC-6036/RG6330Phase INCT04449874KRASG12CAstraZenecaAZD4625Phase IPendingKRASG12CNovartisJDQ443Phase INCT04699188KRASG12CJacobioJAB-21000PreclinicalN/AKRASG12DJacobioJAB-22000PreclinicalN/AKRASG12VJacobioJAB-23000PreclinicalN/AKRASBridgeBioBBP-454PreclinicalN/AKRASG12CLillyLY3537982PreclinicalN/AKRASG12CLillyLY3499446DiscontinuedNCT04165031KRASG12CJanssenJNJ-74699157DiscontinuedNCT04006301KRAS, viral homolog; N/A, appli
Language: Английский
Citations
222
Cancer Treatment Reviews, Journal Year: 2021, Volume and Issue: 99, P. 102237 - 102237
Published: May 29, 2021
Language: Английский
Citations
215
Nature Cancer, Journal Year: 2021, Volume and Issue: 2(3), P. 271 - 283
Published: March 24, 2021
Language: Английский
Citations
201
Journal of Thoracic Oncology, Journal Year: 2021, Volume and Issue: 17(2), P. 309 - 323
Published: Oct. 8, 2021
Language: Английский
Citations
199
Advanced Drug Delivery Reviews, Journal Year: 2021, Volume and Issue: 176, P. 113891 - 113891
Published: July 26, 2021
CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-associated protein 9) is a potent technology for gene-editing. Owing to its high specificity and efficiency, extensity used human diseases treatment, especially cancer, which involves multiple genetic alterations. Different concepts of cancer treatment by are established. However, significant challenges remain clinical applications. The greatest challenge therapy how safely efficiently deliver it target sites in vivo. Nanotechnology has greatly contributed drug delivery. Here, we present the action mechanisms CRISPR/Cas9, application focus on nanotechnology-based delivery gene editing immunotherapy pave way translation. We detail difficult barriers CRISIR/Cas9 vivo discuss relative solutions encapsulation, delivery, controlled release, cellular internalization, endosomal escape.
Language: Английский
Citations
181
Critical Reviews in Oncology/Hematology, Journal Year: 2021, Volume and Issue: 163, P. 103374 - 103374
Published: June 2, 2021
Language: Английский
Citations
177
International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(11), P. 5421 - 5421
Published: May 21, 2021
Inflammation, especially chronic inflammation, plays a pivotal role in tumorigenesis and metastasis through various mechanisms is now recognized as hallmark of cancer an attractive therapeutic target cancer. In this review, we discuss recent advances molecular how inflammation promotes suppresses anti-tumor immunity types solid tumors, including esophageal, gastric, colorectal, liver, pancreatic well hematopoietic malignancies.
Language: Английский
Citations
176
Nucleic Acids Research, Journal Year: 2019, Volume and Issue: unknown
Published: Nov. 6, 2019
Abstract An integrative multi-omics database is needed urgently, because focusing only on analysis of one-dimensional data falls far short providing an understanding cancer. Previously, we presented DriverDB, a cancer driver gene that applies published bioinformatics algorithms to identify genes/mutations. The updated DriverDBv3 (http://ngs.ym.edu.tw/driverdb) designed interpret omics’ sophisticated information with concise visualization. To offer diverse insights into molecular dysregulation/dysfunction events, incorporated computational tools define CNV and methylation drivers. Further, four new features, CNV, Methylation, Survival, miRNA, allow users explore the relations from two perspectives in ‘Cancer’ ‘Gene’ sections. ‘Survival’ panel offers not significant survival genes, but pairs synergistic effects determine. A fresh function, ‘Survival Analysis’ ‘Customized-analysis,’ allows investigate co-occurring events user-defined gene(s) by mutation status or expression specific patient group. Moreover, redesigned web interface provided interactive figures information, also constructed Summary sections visualize features levels concisely. seeks improve study omics identifying genes contributes biology.
Language: Английский
Citations
164
Lung Cancer, Journal Year: 2021, Volume and Issue: 154, P. 161 - 175
Published: Feb. 22, 2021
The discovery of oncogenic driver mutations rendering non-small cell lung cancer (NSCLC) targetable by small-molecule inhibitors, and the development immunotherapies, have revolutionised NSCLC treatment. Today, instead non-selective chemotherapies, all patients with advanced eligible for treatment (and increasing numbers earlier, less extensive disease) require fast comprehensive screening biomarkers first-line patient selection targeted therapy, chemotherapy, or immunotherapy (with without chemotherapy). To avoid unnecessary re-biopsies, biomarker before should also include markers that are actionable from second-line onwards; PD-L1 expression testing is mandatory initiating Population differences exist in frequency mutations: EGFR more frequent Asia than Europe, whereas converse true KRAS mutations. In addition to approved therapies, a number emerging therapies being investigated clinical trials. Guidelines vary country, targets requirement molecular strategies expected increase. meet diagnostic demands, rapid technologies single-driver been implemented. Improvements DNA- RNA-based next-generation sequencing enable analysis group genes one assay; however, turnaround times remain relatively long. Consequently, implemented alongside sequencing. Further challenges evolving landscape primary secondary resistance mechanisms therapies. Therefore, on collected at time disease progression, combination circulating tumour DNA may provide important information guide second- third-line Furthermore, longitudinal can insights into evolution heterogeneity during course disease. We summarise best practice Europe changing diagnosis
Language: Английский
Citations
163
Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11
Published: June 7, 2021
A patient’s response to immune checkpoint inhibitors (ICIs) is a complex quantitative trait, and determined by multiple intrinsic extrinsic factors. Three currently FDA-approved predictive biomarkers (progra1mmed cell death ligand-1 (PD-L1); microsatellite instability (MSI); tumor mutational burden (TMB)) are routinely used for patient selection ICI in clinical practice. Although utility of these has been demonstrated ample trials, many variables involved using have poised serious challenges daily Furthermore, the predicted responders three only small percentage overlap, suggesting that each biomarker captures different contributing factors response. Optimized use development new generation urgently needed. In this review, we will first discuss widely their optimal use. Secondly, review four novel gene signature biomarkers: T-cell inflamed expression profile (GEP), dysfunction exclusion (TIDE), melanocytic plasticity (MPS) B-cell focused signature. The GEP TIDE shown better performance than PD-L1, PD-L1 or TMB, respectively. MPS superior TIDE. represents previously unexplored Thirdly, highlight two combined TMB+GEP MPS+TIDE. These integrated showed improved outcomes compared single predictor. Finally, present potential nucleic acid signature, allowing DNA RNA be analyzed one assay. This comprehensive could represent future direction developing robust biomarkers, particularly cold tumors,
Language: Английский
Citations
159