Review
Immunology
Xuan Wu, Wenping Song, Cheng Cheng, Ziyang Liu, Xiang Li, Yu Cui, Yao Gao, Ding Li
Summary: Three isoforms of RAS gene, KRAS, NRAS, and HRAS, are the most mutated family of small GTPases in cancer. While targeted immunotherapies have improved the survival of patients with non-KRAS-mutant cancer, RAS-mutant cancers still have a poor prognosis due to their high aggressiveness. However, recent advances in the use of allele-specific covalent inhibitors have led to the development of effective pharmacological interventions against RAS-mutant cancer, such as Sotorasib (AMG510) for KRAS-G12C mutant NSCLC. This review summarizes the progress and promise of small-molecule inhibitors in clinical trials to improve the prognosis of tumors with RAS mutations.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Medicine, Research & Experimental
Zhe Zhang, Xiaobo Wang, Jiajun Ye, Huanhuan Liu, Jianyang Fang, Mingru Zhang, Yesen Li, Jinxiong Huang, Deliang Zhang, Jing Wang, Xianzhong Zhang
Summary: Researchers have successfully developed radiolabeled small molecules for direct imaging of the KRAS G12C mutation status in tumors, allowing for the first-time screening of the mutation in vivo.
MOLECULAR PHARMACEUTICS
(2021)
Editorial Material
Oncology
Christina Guo, Udai Banerji
Summary: KRAS mutations play a critical role in cancer, with drugs targeting KRAS(G12C) mutations showing potential efficacy. Clinical trials targeting non-G12C mutated KRAS driven cancers with the dual RAF-MEK inhibitor VS-6766 have shown early single agent activity.
BRITISH JOURNAL OF CANCER
(2021)
Article
Chemistry, Organic
Jie Xu, Ngiap-Kie Lim, Jacob C. Timmerman, Jeff Shen, Kyle Clagg, Ugo Orcel, Raphael Bigler, Etienne Trachsel, Roland Meier, Nicholas A. White, Johannes A. Burkhard, Lauren E. Sirois, Qingping Tian, Remy Angelaud, Stephan Bachmann, Haiming Zhang, Francis Gosselin
Summary: A chromatography-free asymmetric synthesis of GDC-6036 was achieved via a highly atroposelective Negishi coupling reaction. The key intermediate, (Ra)-3, was obtained through the coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol% [Pd(cin)Cl]2 and 1 mol% (R,R)-Chiraphite. The final product, high-purity GDC-6036, was obtained through controlled acrylamide installation and adipate salt formation.
Review
Pharmacology & Pharmacy
Lala S. Rathod, Pratap S. Dabhade, Santosh N. Mokale
Summary: KRASG12C has been identified as a potential target in the treatment of solid tumors, and despite being considered an 'undrugable' target for a long time, sustained research efforts on the KRASG12C mutant protein have achieved promising results. The FDA has granted emergency approval for sotorasib and adagrasib for the treatment of metastatic lung cancer, sparking new approaches to KRASG12C.
DRUG DISCOVERY TODAY
(2023)
Article
Chemistry, Analytical
John C. Tran, Thomas Hunsaker, Christina Bell, Taylur P. Ma, Emily Chan, Pablo Saenz-Lopez Larrocha, Kelsey Homyk, Liling Liu, Hank La, Jialin Mao, Cecile C. de la Cruz, Kebing Yu, Maureen Beresini, William F. Forrest, Yang Xiao, Anne Jang, Natalia Samus, Nicholas Dupuis Stesco, Marija Mentinova, Stephane Parent, Gwenael Pottiez, Michael Schirm, Hans E. Purkey, Yichin Liu, Mark Merchant
Summary: The growing opportunities for covalent drug inhibitors, such as KRAS G12C inhibitors, have driven the need for mass spectrometry methods to measure therapeutic drug activity in vivo efficiently. In this study, an automated and integrated sample preparation method was described to measure the activity levels of KRAS G12C drug inhibitor alkylation from complex tumor samples. The method showed reliable results with low variation, enabling a better understanding of the relationship between KRAS G12C target occupancy and therapeutic effects.
ANALYTICAL CHEMISTRY
(2023)
Article
Oncology
Susmita Ghosh, Fan Fan, Reid T. Powell, Jason Roszik, Yong Sung Park, Clifford Stephan, Manu Sebastian, Lin Tan, Alexey Sorokin, Philip L. Lorenzi, Scott Kopetz, Lee M. Ellis, Rajat Bhattacharya
Summary: Mutations in KRAS are common in metastatic colorectal cancer (mCRC) and direct targeting of these mutations is difficult. In this study, we found that the combination of trametinib and vincristine showed significant efficacy in inhibiting tumor growth and inducing apoptosis in KRAS-mutant colorectal cancer. The combination also inhibited the RAS-RAF-MEK and PI3K-AKT-mTOR survival pathways.
MOLECULAR CANCER THERAPEUTICS
(2023)
Article
Oncology
Thomas McFall, Michael Trogdon, Anita C. Guizar, John F. Langenheim, Laura Sisk-Hackworth, Edward C. Stites
Summary: The combination of KRAS G12C inhibitors with EGFR inhibitors has shown consistent benefits, including inhibiting both wild-type and mutant RAS.
NPJ PRECISION ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shudong Niu, Kaixin Cheng, Longzhong Jia, Jing Liang, Lu Mu, Yibo Wang, Xuebing Yang, Chen Yang, Yan Zhang, Chao Wang, Lijun Huang, Huarong Wang, Shuang Zhang, Hua Zhang
Summary: This study demonstrated that ovarian granulosa cell tumors (GCTs) originate from mutant granulosa cells (GCs) and identified the upregulation of immune evasion genes Cd24a and Cd47 as a mechanism for the transition of mutant GCs to GCTs. Treatment with the Cd47 inhibitor RRX-001 effectively suppressed GCT growth in vivo.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Cell Biology
Xiaofei Zhang, Tiebo Mao, Haiyan Xu, Shumin Li, Ming Yue, Jingyu Ma, Jiayu Yao, Yongchao Wang, Xiao Zhang, Weiyu Ge, Yanling Wang, Daiyuan Shentu, Liwei Wang
Summary: The combination treatment of Trametinib and JQ1 shows synergistic effects in KRAS mutant pancreatic cancer cells, inhibiting cell proliferation. Moreover, the combination therapy may induce different cell death modes in different pancreatic cancer subtypes.
Review
Chemistry, Medicinal
Claudia Korzeniecki, Ronny Priefer
Summary: KRAS genes are commonly mutated in cancer, and targeting KRAS mutant cancers has proven difficult due to lack of success with direct inhibitors. Researchers are now focusing on targeting other areas of the MAPK signaling pathway to inhibit KRAS function.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Oncology
Noah C. Cheng, Robert H. Vonderheide
Summary: The long-held desire to target the mutant KRAS gene therapeutically is being fulfilled with the development of small-molecule inhibitors. In addition to its role as a therapeutic target, KRAS also plays a crucial role in shaping the immunosuppressive nature of the tumor microenvironment. This opens up new possibilities for combination immunotherapy using mKRAS inhibitors.
Article
Biochemistry & Molecular Biology
Kristie-Ann Dickson, Tao Xie, Christian Evenhuis, Yue Ma, Deborah J. Marsh
Summary: PARP inhibitors have shown efficacy in treating tumors with BRCA gene defects, improving survival outcomes. Variability exists between different PARP inhibitors in terms of chemical structure, toxicity, and cell survival, with acquired resistance being a concerning issue that needs further exploration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Nanoscience & Nanotechnology
Ran Li, Thomas S. C. Ng, Stephanie J. Wang, Mark Prytyskach, Christopher B. Rodell, Hannes Mikula, Rainer H. Kohler, Michelle A. Garlin, Douglas A. Lauffenburger, Sareh Parangi, Daniela M. Dinulescu, Nabeel Bardeesy, Ralph Weissleder, Miles A. Miller
Summary: The study demonstrates that the accumulation of nanoparticle albumin bound paclitaxel in tumors is influenced by signaling molecules related to nutrient uptake and processing, which can be reprogrammed to enhance the drug's efficacy.
NATURE NANOTECHNOLOGY
(2021)
Article
Oncology
Vikki Flemington, Emma J. Davies, David Robinson, Linda C. Sandin, Oona Delpuech, Pei Zhang, Lyndsey Hanson, Paul Farrington, Sigourney Bell, Katarzyna Falenta, Francis D. Gibbons, Nicola Lindsay, Aaron Smith, Joanne Wilson, Karen Roberts, Michael Tonge, Philip Hopcroft, Sophie E. Willis, Martine P. Roudier, Claire Rooney, Elizabeth A. Coker, Patricia Jaaks, Mathew J. Garnett, Stephen E. Fawell, Clifford D. Jones, Richard A. Ward, Iain Simpson, Sabina C. Cosulich, J. Elizabeth Pease, Paul D. Smith
Summary: The RAS/MAPK signaling pathway plays a key role in oncogenesis, often dysregulated by mutations in BRAF or RAS genes. Combination of ERK1/2 and MEK1/2 inhibitors shows promising efficacy in KRAS-mutant tumors, providing deeper and more durable suppression of the pathway signaling and resulting in significant tumor regressions in preclinical models. This combination represents a viable clinical approach to target KRAS-mutant tumors.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Multidisciplinary Sciences
Jay W. Kim, Susan H. Brawley, Simon Prochnik, Mansi Chovatia, Jane Grimwood, Jerry Jenkins, Kurt LaButti, Konstantinos Mavromatis, Matt Nolan, Matthew Zane, Jeremy Schmutz, John W. Stiller, Arthur R. Grossman
Article
Genetics & Heredity
Marcel Huntemann, Natalia N. Ivanova, Konstantinos Mavromatis, H. James Tripp, David Paez-Espino, Kristin Tennessen, Krishnaveni Palaniappan, Ernest Szeto, Manoj Pillay, I-Min A. Chen, Amrita Pati, Torben Nielsen, Victor M. Markowitz, Nikos C. Kyrpides
STANDARDS IN GENOMIC SCIENCES
(2016)
Correction
Genetics & Heredity
Marcel Huntemann, Natalia N. Ivanova, Konstantinos Mavromatis, H. James Tripp, David Paez-Espino, Krishnaveni Palaniappan, Ernest Szeto, Manoj Pillay, I-Min A. Chen, Amrita Pati, Torben Nielsen, Victor M. Markowitz, Nikos C. Kyrpides
STANDARDS IN GENOMIC SCIENCES
(2016)
Article
Genetics & Heredity
Irina Panschin, Sixing Huang, Jan P. Meier-Kolthoff, Brian J. Tindall, Manfred Rohde, Susanne Verbarg, Alla Lapidus, James Han, Stephan Trong, Matthew Haynes, T. B. K. Reddy, Marcel Huntemann, Amrita Pati, Natalia N. Ivanova, Konstantinos Mavromatis, Victor Markowitz, Tanja Woyke, Markus Goeker, Hans-Peter Klenk, Nikos C. Kyrpides, Richard L. Hahnke
STANDARDS IN GENOMIC SCIENCES
(2016)
Article
Multidisciplinary Sciences
Manu N. Capoor, Filip Ruzicka, Jonathan E. Schmitz, Garth A. James, Tana Machackova, Radim Jancalek, Martin Smrcka, Radim Lipina, Fahad S. Ahmed, Todd F. Alamin, Neel Anand, John C. Baird, Nitin Bhatia, Sibel Demir-Deviren, Robert K. Eastlack, Steve Fisher, Steven R. Garfin, Jaspaul S. Gogia, Ziya L. Gokaslan, Calvin C. Kuo, Yu-Po Lee, Konstantinos Mavrommatis, Elleni Michu, Hana Noskova, Assaf Raz, Jiri Sana, A. Nick Shamie, Philip S. Stewart, Jerry L. Stonemetz, Jeffrey C. Wang, Timothy F. Witham, Michael F. Coscia, Christof Birkenmaier, Vincent A. Fischetti, Ondrej Slaby
Article
Hematology
Brian A. Walker, Konstantinos Mavrommatis, Christopher P. Wardell, T. Cody Ashby, Michael Bauer, Faith E. Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Philippe Moreau, Brian Durie, A. Keith Stewart, Hartmut Goldschmidt, Marc S. Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H. Jackson, Kenneth C. Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth J. Morgan
Article
Oncology
Brian A. Walker, Konstantinos Mavrommatis, Christopher P. Wardell, T. Cody Ashby, Michael Bauer, Faith Davies, Adam Rosenthal, Hongwei Wang, Pingping Qu, Antje Hoering, Mehmet Samur, Fadi Towfic, Maria Ortiz, Erin Flynt, Zhinuan Yu, Zhihong Yang, Dan Rozelle, John Obenauer, Matthew Trotter, Daniel Auclair, Jonathan Keats, Niccolo Bolli, Mariateresa Fulciniti, Raphael Szalat, Phillipe Moreau, Brian Durie, A. Keith Stewart, Hartmut Goldschmidt, Marc S. Raab, Hermann Einsele, Pieter Sonneveld, Jesus San Miguel, Sagar Lonial, Graham H. Jackson, Kenneth C. Anderson, Herve Avet-Loiseau, Nikhil Munshi, Anjan Thakurta, Gareth Morgan
Correction
Hematology
B. A. Walker, K. Mavrommatis, C. P. Wardell
Article
Multidisciplinary Sciences
Manu N. Capoor, Filip Ruzicka, Tana Machackova, Radim Jancalek, Martin Smrcka, Jonathan E. Schmitz, Marketa Hermanova, Jiri Sana, Elleni Michu, John C. Baird, Fahad S. Ahmed, Karel Maca, Radim Lipina, Todd F. Alamin, Michael F. Coscia, Jerry L. Stonemetz, Timothy Witham, Garth D. Ehrlich, Ziya L. Gokaslan, Konstantinos Mavrommatis, Christof Birkenmaier, Vincent A. Fischetti, Ondrej Slaby
Article
Multidisciplinary Sciences
Manu N. Capoor, Filip Ruzicka, Gurpreet Sandhu, Jess Rollason, Konstantinos Mavrommatis, Fahad S. Ahmed, Jonathan E. Schmitz, Assaf Raz, Holger Bruggemann, Peter A. Lambert, Vincent A. Fischetti, Ondrej Slaby
Article
Hematology
Naser Ansari-Pour, Mehmet Samur, Erin Flynt, Sarah Gooding, Fadi Towfic, Nicholas Stong, Maria Ortiz Estevez, Konstantinos Mavrommatis, Brian Walker, Gareth Morgan, Nikhil Munshi, Herve Avet-Loiseau, Anjan Thakurta
Summary: Large-scale analysis of relapsed/refractory multiple myeloma (rrMM) shows significant genomic variation compared to newly diagnosed multiple myeloma (ndMM). This variation may be associated with therapeutic exposures and clonal structure. Genomic aberrations associated with resistance to immunomodulatory agent (IMiD) therapy are identified and their role in therapy evasion should be further evaluated.
Article
Microbiology
Faten Ghodhbane-Gtari, Nicholas Beauchemin, Moussa Louati, Imen Nouioui, Amir Ktari, Karima Hezbri, Abdellatif Gueddou, Amy Chen, Marcel Huntemann, Natalia Ivanova, Nikos Kyrpides, Victor Markowitz, Kostas Mavrommatis, Ioanna Pagani, Arnab Sen, Luis Wall, Tanja Woyke, Maher Gtari, Louis S. Tisa
GENOME ANNOUNCEMENTS
(2016)
Article
Microbiology
Faten Ghodhbane-Gtari, Nicholas Beauchemin, Abdellatif Gueddou, Karima Herbri, Amir Ktari, Moussa Louati, Imen Nouioui, Amy Chen, Marcel Huntemann, Natalia Ivanova, Nikos Kyrpides, Victor Markowitz, Kostas Mavrommatis, Ioanna Pagani, Arnab Sen, Luis Wall, Tanja Woyke, Maher Gtari, Louis S. Tisa
GENOME ANNOUNCEMENTS
(2016)
Article
Microbiology
Louis S. Tisa, Nicholas Beauchemin, Michael N. Cantor, Teal Furnholm, Faten Ghodhbane-Gtari, Lynne Goodwin, Alex Copeland, Maher Gtari, Marcel Huntemann, Natalia Ivanova, Nikos Kyrpides, Victor Markowitz, Kostas Mavrommatis, Natalia Mikhailova, Imen Nouioui, Rediet Oshone, Galina Ovchinnikova, Ioanna Pagani, Krishnaveni Palaniappan, Amrita Pati, Arnab Sen, Nicole Shapiro, Ernest Szeto, Luis Wall, Jessie Wishart, Tanja Woyke
GENOME ANNOUNCEMENTS
(2015)