Generic placeholder image

Recent Patents on Anti-Cancer Drug Discovery

Editor-in-Chief

ISSN (Print): 1574-8928
ISSN (Online): 2212-3970

Review Article

KRAS Pathways: A Potential Gateway for Cancer Therapeutics and Diagnostics

Author(s): Pankaj Kumar Tripathi, Khushi R. Mittal, Nandini Jain, Naveen Sharma and Chakresh Kumar Jain*

Volume 19, Issue 3, 2024

Published on: 11 May, 2023

Page: [268 - 279] Pages: 12

DOI: 10.2174/1574892818666230406085120

Price: $65

Abstract

One of the major disturbing pathways within cancer is “The Kirsten rat sarcoma viral oncogene homolog (KRAS) pathway”, and it has recently been demonstrated to be the most crucial in therapies and diagnostics. KRAS pathway includes numerous genes. This multi-component signaling system promotes cell growth, division, survival, and death by transferring signals from outside the cell to its interior. KRAS regulates the activation of a variety of signaling molecules. The KRAS oncogene is a key player in advancing a wide range of malignancies, and the mutation rank of this gene is a key feature of several tumors. For some malignancies, the mutation type of the gene may offer information about prognostic, clinical, and predictive. KRAS belongs to the RAS oncogene family, which consists of a compilation of minor GTP-binding proteins that assimilate environmental inputs and trigger internal signaling pathways that control survival, cell differentiation, and proliferation. This review aims to examine the recent and fascinating breakthroughs in the identification of new therapies that target KRAS, including the ever-expanding experimental approaches for reducing KRAS activity and signaling as well as direct targeting of KRAS. A literature survey was performed. All the relevant articles and patents related to the KRAS pathway, the mutation in the KRAS gene, cancer treatment, and diagnostics were found on PubMed and Google Patents. One of the most prevalent causes of cancer in humans is a mutation in the K-RAS protein. It is extremely difficult to decipher KRAS-mediated signaling. It allows transducing signals to go from the cell's outer surface to its nucleus, having an influence on a variety of crucial cellular functions including cell chemotaxis, division, dissemination, and cell death. Other involved signaling pathways are RAF, and the phosphatidylinositol 3 kinase also known as AKT. The EGFR pathway is incomplete without KRAS. The activation of PI3K significantly contributes to acquiring resistance to a mixture of MEK inhibitors and anti-EGFR in colorectal cancer cell lines which are mutated by KRAS. A series of recent patent studies towards cancer diagnostics and therapeutics reveals the paramount importance of mutated protein KRAS as an extensive driver in human tumors. For the prognosis, diagnosis, and treatment of colorectal cancer, KRAS plays a critical role. This review concludes the latest and vowing developments in the discovery of novel techniques for diagnosis and drugs that target KRAS, the advancements in experimental techniques for signaling and inhibiting KRAS function, and the direct targeting of KRAS for cancer therapeutics.

Keywords: Colorectal cancer, KRAS, anemia, EGFR pathway, c-Raf, malignancies, apoptosis.

[1]
Nagasaka, M.; Potugari, B.; Nguyen, A.; Sukari, A.; Azmi, A. S.; Ou, S.-H. I. KRAS Inhibitors- Yes but What next? Direct Targeting of KRAS- Vaccines, Adoptive T Cell Therapy and Beyond. Cancer Treat. Rev., 2021, 101 (102309), 102309.
[http://dx.doi.org/10.1016/j.ctrv.2021.102309]
[2]
Zhu, G.; Pei, L.; Xia, H.; Tang, Q.; Bi, F. Role of Oncogenic KRAS in the Prognosis, Diagnosis and Treatment of Colorectal Cancer. Mol. Cancer., 2021, 20 (1), 143.
[http://dx.doi.org/10.1186/s12943-021-01441-4]
[3]
Huang, L.; Guo, Z.; Wang, F.; Fu, L. KRAS Mutation: From Undruggable to Druggable in Cancer. Signal Transduct. Target. Ther., 2021, 6 (1), 386.
[http://dx.doi.org/10.1038/s41392-021-00780-4]
[4]
Porru, M.; Pompili, L.; Caruso, C.; Biroccio, A.; Leonetti, C. Targeting KRAS in metastatic colorectal cancer: Current strategies and emerging opportunities. J. Exp. Clin. Cancer Res., 2018, 37 (1)
[http://dx.doi.org/10.1186/s13046-018-0719-1]
[5]
Asimgil, H.; Ertetik, U.; Çevik, N. C.; Ekizce, M.; Doğruöz, A.; Gökalp, M.; Arık-Sever, E.; Istvanffy, R.; Friess, H.; Ceyhan, G. O.; Demir, I. E. Targeting the Undruggable Oncogenic KRAS: The Dawn of Hope. JCI Insight., 2022, 7 (1)
[http://dx.doi.org/10.1172/jci.insight.153688]
[6]
Cox, A. D.; Fesik, S. W.; Kimmelman, A. C.; Luo, J.; Der, C. J. Drugging the Undruggable RAS: Mission Possible? Nat. Rev. Drug Discov., 2014, 13 (11), 828-851.
[http://dx.doi.org/10.1038/nrd4389]
[7]
Zhu, C.; Guan, X.; Zhang, X.; Luan, X.; Song, Z.; Cheng, X.; Zhang, W.; Qin, J.-J. Targeting KRAS Mutant Cancers: From Druggable Therapy to Drug Resistance. Mol. Cancer., 2022, 21 (1), 159.
[http://dx.doi.org/10.1186/s12943-022-01629-2]
[8]
Liu, X.; Jakubowski, M.; Hunt, J. L. KRAS Gene Mutation in Colorectal Cancer Is Correlated with Increased Proliferation and Spontaneous Apoptosis. Am. J. Clin. Pathol., 2011, 135 (2), 245-252.
[http://dx.doi.org/10.1309/AJCP7FO2VAXIVSTP]
[9]
Medical advisory secretariat. KRAS Testing for anti-EGFR therapy in advanced colorectal cancer: An Evidence-based and economic analysis. Ont. Health Technol. Assess. Ser., 2010, 10 (25), 1-49.
[http://dx.doi.org/10.1093/annonc/mdw235]
[10]
Wennerberg, K.; Rossman, K. L.; Der, C. J. The Ras Superfamily at a Glance. J. Cell Sci., 2005, 118 (Pt 5), 843-846.
[http://dx.doi.org/10.1242/jcs.01660]
[11]
Hancock, J. F.; Prior, I. A. Electron Microscopic Imaging of Ras Signaling Domains. Methods., 2005, 37 (2), 165-172.
[http://dx.doi.org/10.1016/j.ymeth.2005.05.018]
[12]
Molina, J. R.; Adjei, A. A. The Ras/RAF/MAPK Pathway. J. Thorac. Oncol., 2006, 1 (1), 7-9.
[http://dx.doi.org/10.1016/s1556-0864(15)31506-9]
[13]
Bos, J. L.; Rehmann, H.; Wittinghofer, A. GEFs and GAPs: Critical Elements in the Control of Small G Proteins. Cell., 2007, 130(2), 385.
[http://dx.doi.org/10.1016/j.cell.2007.07.001]
[14]
Jančík, S.; Drábek, J.; Radzioch, D.; Hajdúch, M. Clinical Relevance of KRAS in Human Cancers. J. Biomed. Biotechnol., 2010, 2010, 1-13.
[http://dx.doi.org/10.1155/2010/150960]
[15]
Simanshu, D. K.; Nissley, D. V.; McCormick, F. RAS Proteins and Their Regulators in Human Disease. Cell., 2017, 170 (1), 17-33.
[http://dx.doi.org/10.1016/j.cell.2017.06.009]
[16]
Castellano, E.; Downward, J. RAS Interaction with PI3K: More than Just Another Effector Pathway. Genes Cancer., 2011, 2 (3), 261-274.
[http://dx.doi.org/10.1177/1947601911408079]
[17]
Knickelbein, K.; Zhang, L. Lin Zhang: Mutant KRAS as a Critical Determinant of Thetherapeutic Response of Colorectal Cancer.
[18]
Wee, S.; Jagani, Z.; Xiang, K. X.; Loo, A.; Dorsch, M.; Yao, Y.-M.; Stegmeier, F. PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers. Cancer Research., 2009, 69 (10), 4286-4293.
[19]
Downward, J. Targeting RAS Signalling Pathways in Cancer Therapy. Nat. Rev. Cancer., 2003, 3 (1), 11-22.
[http://dx.doi.org/10.1038/nrc969]
[20]
Li, J.; Yen, C.; Liaw, D.; Podsypanina, K.; Bose, S.; Wang, S. I.; Puc, J.; Miliaresis, C.; Rodgers, L.; McCombie, R.; Bigner, S. H.; Giovanella, B. C.; Ittmann, M.; Tycko, B.; Hibshoosh, H.; Wigler, M. H.; Parsons, R. PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer. Science. 1997, 275 (5308), 1943-1947.
[http://dx.doi.org/10.1126/science.275.5308.1943]
[21]
Glading, A.; Koziol, J. A.; Krueger, J.; Ginsberg, M. H. PEA-15 Inhibits Tumor Cell Invasion by Binding to Extracellular Signal Regulated Kinase 1/2. Cancer Res., 2007, 67 (4), 1536-1544.
[22]
Mebratu, Y. A.; Dickey, B. F.; Evans, C.; Tesfaigzi, Y. The BH3-Only Protein Bik/Blk/Nbk Inhibits Nuclear Translocation of Activated ERK1/2 to Mediate Ifnγ-Induced Cell Death. J. Cell Biol., 2008, 183 (3), 429-439.
[23]
Chuderland, D.; Konson, A.; Seger, R. Identification and Characterization of a General Nuclear Translocation Signal in Signaling Proteins. Mol. Cell., 2008, 31 (6), 850-861.
[http://dx.doi.org/10.1016/j.molcel.2008.08.007]
[24]
Casar, B.; Pinto, A.; Crespo, P. Essential Role of ERK Dimers in the Activation of Cytoplasmic but Not Nuclear Substrates by ERKScaffold Complexes. Mol. Cell., 2008, 31 (5), 708-721.
[http://dx.doi.org/10.1016/j.molcel.2008.07.024]
[25]
Dhanasekaran, D. N.; Kashef, K.; Lee, C. M.; Xu, H.; Reddy, E. P. Scaffold Proteins of MAP-Kinase Modules. Oncogene., 2007, 26 (22), 3185-3202.
[http://dx.doi.org/10.1038/sj.onc.1210411]
[26]
Casar, B.; Arozarena, I.; Sanz-Moreno, V.; Pinto, A.; Agudo-Ibáñez, L.; Marais, R.; Lewis, R. E.; Berciano, M. T.; Crespo, P. Ras Subcellular Localization Defines Extracellular Signal- Regulated Kinase 1 and 2 Substrate Specificity through Distinct Utilization of Scaffold Proteins. Mol. Cell. Biol., 2009, 29 (5), 1338-1353.
[http://dx.doi.org/10.1128/MCB.01359-08]
[27]
Teis, D.; Wunderlich, W.; Huber, L. A. Localization of the MP1-MAPK Scaffold Complex to Endosomes Is Mediated by P14 and Required for Signal Transduction. Dev. Cell., 2002, 3(6), 803-814.
[http://dx.doi.org/10.1016/s1534-5807(02)00364-7]
[28]
Witzel, F.; Maddison, L.; Blüthgen, N. How Scaffolds Shape MAPK Signaling: What We Know and Opportunities for Systems Approaches. Front. Physiol., 2012, 3.
[http://dx.doi.org/10.3389/fphys.2012.00475]
[29]
Filbert, E. L.; Nguyen, A.; Markiewicz, M. A.; Fowlkes, B. J.; Huang, Y. H.; Shaw, A. S. Kinase Suppressor of Ras 1 Is Required for Full ERK Activation in Thymocytes but Not for Thymocyte Selection. Eur. J. Immunol., 2010, 40(11), 3226-3234.
[http://dx.doi.org/10.1002/eji.201040349]
[30]
Hoon, D. S. B.; Taback, B. DNA Markers for Management of Cancer. 7718364, 2010.https://patents.google.com/patent/US7718364.
[31]
Li, C. J.; Sun, X.; Rogoff, H.; Li, Y. Compositions of Asymmetric Interfering RNA and Uses Thereof. 9328345, 2016.https://patents.google.com/patent/US9328345B2/en.
[32]
Ahlquist, D. A.; Kisiel, J. B.; Taylor, W. R.; Yab, T. C.; Mahoney, D. W. Detecting Neoplasm. 9506116, 2016.https://patents.google.com/patent/US9506116B2/en?oq=US9506116B2.
[33]
June, C. H.; Pure, E.; Wang, L.-C.; Albelda, S.; Scholler, J. Compositions and Methods for Targeting Stromal Cells for the Treatment of Cancer. 9365641, 2016.https://patents.google.com/patent/US9365641B2/en.
[34]
Downing, S. R.; Hawryluk, M. J.; Lipson, D.; Parker, A. N.; Stephens, P. J. KIF5B-RET Fusion Molecules and Uses Thereof. 9297011, 2016.https://patents.google.com/patent/US9297011B2/en.
[35]
DePinho, R. A.; Anderson, K. C.; Carrasco, R. D.; Tonon, G.; Brennan, C.; Shaughnessy, J. D., Jr; Chin, L. Compositions, Kits, and Methods for Identification, Assessment, Prevention, and Therapy of Cancer. 9309564, 2016.https://patents.google.com/patent/US9309564B2/en.
[36]
Weichert, J. P.; Longino, M.; Pinchuk, A. Phospholipid Analogs as Diapeutic Agents and Methods Thereof. 8877159, 2014.https://patents.google.com/patent/US8877159B2/en.
[37]
Kelly, K.; Weissleder, R.; Bardeesy, N. Plectin-1 Targeted Agents for Detection and Treatment of Pancreatic Ductal Adenocarcinoma. 9387265, 2016.https://patents.google.com/patent/US9387265B2/en.
[38]
Yamamoto, H.; Mori, M.; Doki, Y.; Nishimura, J. Colorectal Cancer Drug, and Method for Predicting Prognosis of Colorectal Cancer Patient. 10214743, 2019.https://patents.google.com/patent/US10214743B2/en?oq=US10214743B2.
[39]
Lee, H. J.; Koo, B.; Jang, Y. O.; Liu, H.; Dao, T. N. T.; Lim, S.-B.; Shin, Y. Hot-Spot-Specific Probe (HSSP) for Rapid and Accurate Detection of KRAS Mutations in Colorectal Cancer. Biosensors., 2022, 12(8), 597.
[http://dx.doi.org/10.3390/bios12080597]
[40]
Su, W.-C.; Tsai, Y.-C.; Tsai, H.-L.; Chang, T.-K.; Yin, T.-C.; Huang, C.-W.; Chen, Y.-C.; Li, C.-C.; Chen, P.-J.; Liu, Y.-R.; Hsieh, T.-H.; Wang, J.-Y. Comparison of Next-Generation Sequencing and Polymerase Chain Reaction for Personalized Treatment-Related Genomic Status in Patients with Metastatic Colorectal Cancer. Curr. Issues Mol. Biol., 2022, 44(4), 1552-1563.
[http://dx.doi.org/10.3390/cimb44040106]
[41]
Sedigh, M. A.; Mahmoodzadeh, H.; Fazeli, M. S.; Aghdam, M. H.; Toolabi, L. T. The Potential of PIK3CA, KRAS, BRAF, and APC Hotspot Mutations as a Non-Invasive Detection Method for Colorectal Cancer. Molecular and Cellular Probes., 2022, 63.
[42]
Dinu, D.; Dobre, M.; Panaitescu, E.; Bîrlă, R.; Iosif, C.; Hoara, P.; Caragui, A.; Boeriu, M.; Constantinoiu, S.; Ardeleanu, C. Prognostic Significance of KRAS Gene Mutations in Colorectal Cancer-Preliminary Study. J. Med. Life., 2014, 7 (4), 581-587.
[43]
Fritsche, J.; Weinschenk, T.; Walter, S.; Lewandrowski, P.; Singh, H. Immunotherapy against Several Tumors Including Gastrointestinal and Gastric Cancer. 9101585, 2015.https://patents.google.com/patent/US9101585B2/en?oq=US9101585B2.
[44]
Rao, D.; Wang, Z.; Nemunaitis, J. J.; Senzer, N. Bi-Functional Short-Hairpin RNA (Bi-ShRNA) Specific for Single-Nucleotide KRAS Mutations. 9353373, 2016.https://patents.google.com/patent/US9353373B2/en?oq=US9353373B2.
[45]
Fire, A.; Kostas, S.; Montgomery, M.; Timmons, L.; Xu, S.; Tabara, H.; Driver, S. E.; Mello, C. C. Genetic Inhibition by Double- Stranded RNA. 9102939, 2015.https://patents.google.com/patent/US9102939B2/en?oq=US9102939B2.
[46]
Garcia-Echeverria, C.; Maira, S.-M.; Stuart, D.; Wee, S.; Fritsch, C.; Nagel, T. Combination of (a) A Phosphoinositide 3-Kinase Inhibitor and (b) A Modulator of RAS/RAF/MEK Pathway. 9241939, 2016.https://patents.google.com/patent/US9241939B2/en?oq=US9241939B2.
[47]
Govindan, S. V.; Goldenberg, D. M. Combining Radioimmunotherapy and Antibody-Drug Conjugates for Improved Cancer Therapy. 9272057, 2016.https://patents.google.com/patent/US9272057B2/en?oq=US9272057B2.
[48]
David, P. Combination Therapy of HSP90 Inhibitors with Platinum-Containing Agents. 10500193, 2019.https://patents.google.com/patent/US10500193B2/en?oq=US10500193B2.
[49]
David, C.; Laetitia, S.; Sudarshan, A.; Jacqueline, L. Assays for screening for or identifying an agent or molecule that can block or inhibit AVB3 integrin from forming a complex with KRAS. 9903855, 2018.https://patents.google.com/patent/US9903855B2/en?oq=US9903855B2.
[50]
Lanman, B. A.; Booker, S.; Goodman, C.; Reed, A. B.; Low, J. D.; Wang, H.-L.; Chen, N.; Minatti, A. E.; Wurz, R.; Cee, V. J. Inhibitors of KRAS G12C and Methods of Using the Same. 10640504, 2020.https://patents.google.com/patent/US10640504B2/en?oq=US10640504B2.
[51]
Maecker, H.; Irving, B. Methods of Treating Cancer Using PD-1 Axis Binding Antagonists and MEK Inhibitors. 10646567, 2020.https://patents.google.com/patent/US10646567B2/en?oq=US10646567B2.
[52]
Saha, S.; Welsch, D.; DeCrescenzo, G.; Roix, J. J. Cancer Treatment Using Combinations of ERK and RAF Inhibitors. 10668055, 2020.https://patents.google.com/patent/US10668055B2/en?oq=US10668055B2.
[53]
Fritsche, J.; Weinschenk, T.; Walter, S.; Lewandrowski, P.; Singh, H. Immunotherapy against Several Tumors Including Gastrointestinal and Gastric Cancer. 10420816, 2019.https://patents.google.com/patent/US10420816B1/en?oq=US10420816B.
[54]
McCormick, F.; Renslo, A. R.; Turner, D.; Gysin, S.; Maciag, A. E.; Chertov, O. K-Ras Modulators. 10857140, 2020.https://patents.google.com/patent/US10857140B2/en.
[55]
Kim, P.; Singh, S. Drug Selection for Colorectal Cancer Therapy Using Receptor Tyrosine Kinase Profiling. 10401364, 2019.https://patents.google.com/patent/US10401364B2/en?oq=US10401364B2.
[56]
Stockwell, B. R.; Welsch, M. Multivalent RAS Binding Compounds. 9926293, 2018.https://patents.google.com/patent/US9926293B2/en?oq=US9926293B2.
[57]
Janes, M. R.; Patricelli, M. P.; Li, L.; Ren, P.; Liu, Y. Combination Therapies for Treatment of Cancer. 10111874, 2018.https://patents.google.com/patent/US10111874B2/en?oq=US10111874B2.
[58]
Wanebo, H. J. Compositions and Methods for Treating Cancer. 9974760, 2018.https://patents.google.com/patent/US9974760B2/en?oq=US9974760B2.
[59]
Ostrem, J.; Peters, U.; Shokat, K. M. Compositions and Methods for Treating Cancer. 10023588, 2018.https://patents.google.com/patent/US10023588B2/en?oq=US10023588B2.
[60]
Ren, P.; Liu, Y.; Li, L.; Feng, J.; Wu, T. Covalent Inhibitors of Kras G12C. 9227978, 2016.https://patents.google.com/patent/US9227978B2/en?oq=US9227978B2.
[61]
Proia, D. Cancer Therapy Using a Combination of HSP90 Inhibitors with Topoisomerase I Inhibitors. 9439899, 2016.https://patents.google.com/patent/US9439899B2/en?oq=US9439899B2.
[62]
Danter, W. R. Inhibitor Compounds and Cancer Treatment Methods. 9284275, 2016.https://patents.google.com/patent/US9284275B2/en?oq=US9284275B2.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy