Review
Oncology
Alessandro Di Federico, Ilaria Ricciotti, Valentina Favorito, Sandra Vietti Michelina, Pietro Scaparone, Giulio Metro, Andrea De Giglio, Federica Pecci, Giuseppe Lamberti, Chiara Ambrogio, Biagio Ricciuti
Summary: The recent development of direct KRAS(G12C) inhibitors has improved outcomes in KRAS mutant cancers, but acquired resistance still occurs. The mechanisms of acquired resistance are heterogeneous, involving both on-target and off-target resistance, including mutations in KRAS and other pathways. Understanding and overcoming resistance is important for targeted therapies.
CURRENT ONCOLOGY REPORTS
(2023)
Article
Medicine, General & Internal
Adrian Sacher, Patricia LoRusso, Manish R. Patel, Wilson H. Miller, Elena Garralda, Martin D. Forster, Armando Santoro, Alejandro Falcon, Tae Won Kim, Luis Paz-Ares, Samantha Bowyer, Maria de Miguel, Sae-Won Han, Matthew G. Krebs, Jong-Seok Lee, Michael L. Cheng, Kathryn Arbour, Erminia Massarelli, Yoonha Choi, Zhen Shi, Sandhya Mandlekar, Mark T. Lin, Stephanie Royer-Joo, Julie Chang, Neekesh V. Dharia, Jennifer L. Schutzman, Jayesh Desai
Summary: Divarasib, a KRAS G12C inhibitor, has shown promising therapeutic effects with minimal adverse events in patients with tumors harboring the KRAS G12C mutation.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Review
Oncology
Cian O'Leary, Grace Murphy, Yong Yeung, Ming Tang, Vikram Jain, Connor G. O'Leary
Summary: Non-small-cell lung cancer (NSCLC) is a common and often fatal malignancy, with Kirsten rat sarcoma virus (KRAS) mutation being a commonly mutated oncogene in NSCLC. Recently developed KRAS G12C inhibitors have overcome the therapeutic hurdle of targeting KRAS mutations. While these medications show substantial response rates in heavily pre-treated NSCLC patients, phase-3 evidence has not yet demonstrated an overall survival benefit compared to standard-of-care chemotherapy. Additionally, these medications may have a negative interaction with immunotherapies, leading to higher hepatotoxicity rates. Despite these limitations, these medications represent an important advancement in targeted and personalized oncological treatment, and future trials may provide further meaningful outcomes for guiding treatment in this patient cohort.
Review
Oncology
Nabih Naim, Sara Moukheiber, Samah Daou, Hampig Raphael Kourie
Summary: RAS gene, the most frequently mutated oncogene in human cancers, was previously considered undruggable until the emergence of KRAS-G12C inhibitors. Despite the FDA approval of Sotorasib for KRAS-G12C mutated NSCLC, challenges of drug resistance persist, prompting researchers to explore combination strategies for overcoming resistance. Ongoing studies aim to better understand the predictive and prognostic role of KRAS-G12C as well as its position in personalized medicine.
CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
(2021)
Article
Multidisciplinary Sciences
Tereza Vaclova, Atanu Chakraborty, James Sherwood, Sarah Ross, Danielle Carroll, J. Carl Barrett, Julian Downward, Elza C. de Bruin
Summary: The study investigates the co-occurrence of additional KRAS mutations with KRAS G12C in non-small cell lung cancer (NSCLC) tumors and its impact on cellular response to G12C-specific inhibitors. The results show that KRAS c.35G>T mutation most frequently co-occurred with KRAS G12C and led to cellular resistance to G12C inhibitors. Therefore, comprehensive genotyping of KRAS tumors is necessary for optimal patient selection for treatment with a KRAS G12C inhibitor.
SCIENTIFIC REPORTS
(2022)
Article
Oncology
Anjali Rohatgi, Ramaswamy Govindan
Summary: Lung cancer remains a major cause of cancer related deaths globally. Specific targeted therapies for driver mutations have shown significant survival benefits, but patients with KRAS mutations lacked such options until the recent FDA approval of sotorasib. This article discusses the efficacy, toxicities, acquired resistance, and novel combinatorial treatment strategies of KRAS G12C inhibitors.
Article
Multidisciplinary Sciences
Atish Mohanty, Arin Nam, Saumya Srivastava, Jeff Jones, Brett Lomenick, Sharad S. Singhal, Linlin Guo, Hyejin Cho, Aimin Li, Amita Behal, Tamara Mirzapoiazova, Erminia Massarelli, Marianna Koczywas, Leonidas D. Arvanitis, Tonya Walser, Victoria Villaflor, Stanley Hamilton, Isa Mambetsariev, Martin Sattler, Mohd W. Nasser, Maneesh Jain, Surinder K. Batra, Raffaella Soldi, Sunil Sharma, Marwan Fakih, Saswat Kumar Mohanty, Avijit Mainan, Xiwei Wu, Yihong Chen, Yanan He, Tsui-Fen Chou, Susmita Roy, John Orban, Prakash Kulkarni, Ravi Salgia
Summary: This study reveals non-genetic mechanisms of resistance to sotorasib and proposes a treatment strategy to enhance sensitivity by targeting both ITGB4 and beta-catenin.
Article
Oncology
Lucia Notario, Marc Cucurull, Gabriela Cerda, Carolina Sanz, Enric Carcereny, Ana Munoz-Marmol, Ainhoa Hernandez, Marta Domenech, Teresa Moran, Montse Sanchez-Cespedes, Marta Costa, Jose-Luis Mate, Anna Esteve, Maria Saigi
Summary: In this study, we found that activating mutations in KRAS are common in lung adenocarcinoma and are associated with alterations in the tumor immune microenvironment. Patients with high PD-L1 expression tumors had better overall survival and progression-free survival regardless of the type of KRAS mutation.
FRONTIERS IN ONCOLOGY
(2023)
Review
Oncology
Marc Cucurull, Lucia Notario, Montse Sanchez-Cespedes, Cinta Hierro, Anna Estival, Enric Carcereny, Maria Saigi
Summary: This review discusses the molecular characteristics and clinical implications of KRAS mutant lung cancers. It highlights the development of specific KRAS G12C inhibitors and other targeted therapies, as well as the impact of tumor heterogeneity and immune regulation on treatment outcomes.
FRONTIERS IN ONCOLOGY
(2022)
Review
Chemistry, Medicinal
Dongqiang Zhao, Yu Liu, Fengchao Yi, Xia Zhao, Kui Lu
Summary: The RAS gene, consisting of KRAS, HRAS, and NRAS, is associated with human tumors, with KRAS having the highest mutation incidence at around 80% of cases. This gene plays a regulatory role in transcription and translation at the molecular level, and affects cell proliferation and migration at the cellular level, making it crucial for cancer development. In 2021, the FDA approved the first direct inhibitor, AMG510, targeting the KRAS-G12C mutation, which showed tumor regression, prolonged survival, and low off-target activity. However, due to drug resistance, single inhibitors are no longer sufficient, leading to the development of numerous highly efficient inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Junmin Zhang, Juanhong Zhang, Qing Liu, Xing-Xing Fan, Elaine Lai-Han Leung, Xiao-Jun Yao, Liang Liu
Summary: KRAS mutations are common in carcinoma, and KRAS G12C inhibitors have exhibited significant clinical responses. However, resistance mechanisms to these inhibitors are diverse and further research is needed.
PHARMACOLOGY & THERAPEUTICS
(2022)
Review
Oncology
Lindor Qunaj, Michael S. May, Alfred I. Neugut, Benjamin O. Herzberg
Summary: KRAS G12C mutations play a critical role in multiple cancer types, but the therapeutic success of KRAS G12C inhibitors is limited in colorectal and pancreatic cancers compared to non-small cell lung cancer. This review summarizes the biochemistry of KRAS targeting and treatment resistance, provides an overview of the published data on KRAS G12C inhibitors for various indications, and discusses ongoing clinical trials and future directions in the management of G12C-mutant colorectal cancer.
FRONTIERS IN ONCOLOGY
(2023)
Review
Pathology
Rajwanth Veluswamy, Philip C. Mack, Jane Houldsworth, Ehab Elkhouly, Fred R. Hirsch
Summary: Mutation in the KRAS gene, particularly the G12C mutation, is a common oncogenic driver in non-small cell lung cancer. Recent advances in molecular modeling have led to the development of direct inhibitors targeting mutant KRas(G12C), offering new therapeutic options for patients with lung adenocarcinoma.
JOURNAL OF MOLECULAR DIAGNOSTICS
(2021)
Article
Oncology
Luiz Henrique Araujo, Bianca Mendes Souza, Laura Rabelo Leite, Sabrina A. F. Parma, Natalia P. Lopes, Frederico S. V. Malta, Maira C. M. Freire
Summary: KRAS G12C mutation frequency is higher than other driver mutations in colorectal and non-small cell lung cancer, suggesting KRAS testing should be considered for all patients regardless of clinical or demographic characteristics.
Editorial Material
Oncology
Sarina Z. W. Heng, Regina Hoo, Daniel S. W. Tan
Summary: Negrao and colleagues demonstrated that coalterations in KEAP1, SMARCA4, and CDKN2A genes were linked to poor clinical outcomes in patients with KRAS (G12C)-mutated non-small cell lung cancer treated with sotorasib or adagrasib. Their study emphasizes the potential of integrating high-resolution real-world genomic data with clinical outcomes to enable risk-stratified precision therapies.
Article
Oncology
Jesse Boumelha, Sophie de Carne Trecesson, Emily K. Law, Pablo Romero-Clavijo, Matthew A. Coelho, Kevin W. Ng, Edurne Mugarza, Christopher Moore, Sareena Rana, Deborah R. Caswell, Miguel Murillo, David C. Hancock, Prokopios P. Argyris, William L. Brown, Cameron Durfee, Lindsay K. Larson, Rachel Vogel, Alejandro Suarez-Bonnet, Simon L. Priestnall, Philip East, Sarah J. Ross, George Kassiotis, Miriam Molina-Arcas, Charles Swanton, Reuben Harris, Julian Downward
Summary: This study develops a mouse model of immunogenic KRAS-mutant lung cancer to facilitate the investigation of optimal combinations of targeted therapies with immunotherapies.
Editorial Material
Medicine, General & Internal
Miriam Molina-Arcas, Julian Downward
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Multidisciplinary Sciences
Edurne Mugarza, Febe van Maldegem, Jesse Boumelha, Christopher Moore, Sareena Rana, Miriam Llorian Sopena, Philip East, Rachel Ambler, Panayiotis Anastasiou, Pablo Romero-Clavijo, Karishma Valand, Megan Cole, Miriam Molina-Arcas, Julian Downward
Summary: Recently developed KRAS(G12C) inhibitory drugs benefit lung cancer patients with KRAS(G12C) mutations, but drug resistance is common. These drugs indirectly affect antitumor immunity by reversing immunosuppression caused by oncogenic KRAS. However, the combination of KRAS(G12C) inhibitors with immune checkpoint blockade only provides synergistic benefit in highly immunogenic tumor models.
Article
Biochemical Research Methods
May Zaw Thin, Christopher Moore, Thomas Snoeks, Tammy Kalber, Julian Downward, Axel Behrens
Summary: In this paper, a method of lung nodule image acquisition and analysis using a micro-computed tomography scanner is introduced for translational research in lung cancer that closely mimics clinical environments. The method has the advantages of low radiation dose, high resolution, and high-throughput imaging, and utilizes specific image analysis tools for identifying different types of lung tumors.
Article
Biochemistry & Molecular Biology
David Ochoa, Andrew Hercules, Miguel Carmona, Daniel Suveges, Jarrod Baker, Cinzia Malangone, Irene Lopez, Alfredo Miranda, Carlos Cruz-Castillo, Luca Fumis, Manuel Bernal-Llinares, Kirill Tsukanov, Helena Cornu, Konstantinos Tsirigos, Olesya Razuvayevskaya, Annalisa Buniello, Jeremy Schwartzentruber, Mohd Karim, Bruno Ariano, Ricardo Esteban Martinez Osorio, Javier Ferrer, Xiangyu Ge, Sandra Machlitt-Northen, Asier Gonzalez-Uriarte, Shyamasree Saha, Santosh Tirunagari, Chintan Mehta, Juan Maria Roldan-Romero, Stuart Horswell, Sarah Young, Maya Ghoussaini, DavidG Hulcoop, Ian Dunham, EllenM McDonagh
Summary: The Open Targets Platform is an open-source resource that facilitates drug target identification and prioritization using publicly available data. It has been redesigned and rebuilt to improve data integration, expand the ways users can explore the data, and enhance the user experience. The platform now includes enhanced gene-disease evidence, new features for assessing target safety and tractability, and machine learning applications for extracting knowledge from literature, clinical trials, and drug labels.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M. Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G. Gutierrez
Summary: This study reveals that limited lysosomal damage leads to changes in the mitochondrial proteome and the modulation of macrophage immunometabolism. It shows that protease leakage from lysosomes triggers a cell death-independent proteolytic remodeling of the mitochondrial proteome in macrophages.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Mohamed Ismail, Stephen R. Martin, Roger George, Francesca Houghton, Geoff Kelly, Raphael A. G. Chaleil, Panayiotis Anastasiou, Xinyue Wang, Nicola O'Reilly, Stefania Federico, Dhira Joshi, Hemavathi Nagaraj, Rachel Cooley, Ning Sze Hui, Miriam Molina-Arcas, David C. Hancock, Ali Tavassoli, Julian Downward
Summary: A cyclic peptide inhibitor (cyclo-CRVLIR) was discovered that interacts with the p110 alpha-RBD and blocks its interaction with KRAS. This inhibitor effectively blocks the p110 alpha/KRAS interaction and reduces phospho-AKT levels in several oncogenic KRAS cell lines.
SCIENTIFIC REPORTS
(2023)
Article
Multidisciplinary Sciences
Kevin Ng, Jesse Boumelha, Katey S. S. Enfield, Jorge L. Almagro, Hongui M. Cha, Oriol Pich, Takahiro Karasaki, David Moore, Roberto Salgado, Monica Sivakumar, George Young, Miriam L. Molina-Arcas, Sophie de Carne Trecesson, Panayiotis Anastasiou, Annika C. Fendler, Lewis Au, Scott T. C. Shepherd, Carlos Martinez-Ruiz, Clare Puttick, James R. M. Black, Thomas B. K. Watkins, Hyemin Kim, Seohee Shim, Nikhil Faulkner, Jan A. Attig, Selvaraju Veeriah, Neil J. Magno, Sophia T. Ward, Alexander Frankell, Maise Al Bakir, Emilia Lim, Mark Hill, Gareth Wilson, Daniel Cook, Nicolai Birkbak, Axel Behrens, Nadia Yousaf, Sanjay Popat, Allan Hackshaw, TRACERx Consortium, CAPTURE Consortium, Crispin T. Hiley, Kevin Litchfield, Nicholas McGranahan, Mariam Jamal-Hanjani, James Larkin, Se-Hoon Lee, Samra Turajlic, Charles Swanton, Julian Downward, George Kassiotis
Summary: This study reveals that lung adenocarcinomas in both humans and mice elicit local germinal center responses and tumour-binding antibodies, with endogenous retrovirus (ERV) envelope glycoproteins as the dominant anti-tumour antibody target. ERV-targeting B cell responses are enhanced by immune checkpoint blockade (ICB) and targeted inhibition of KRAS(G12C). ERV-reactive antibodies have anti-tumour activity and improve survival in a mouse model, and ERV expression predicts the response to ICB in human lung adenocarcinoma. Furthermore, the study demonstrates that effective immunotherapy in the mouse model requires CXCL13-dependent tertiary lymphoid structure (TLS) formation, and therapeutic CXCL13 treatment enhances anti-tumour immunity and synergizes with ICB. These findings provide a potential mechanistic basis for the association between TLS and immunotherapy response.
Article
Multidisciplinary Sciences
William Hill, Emilia L. Lim, Clare E. Weeden, Claudia Lee, Marcellus Augustine, Kezhong Chen, Feng-Che Kuan, Fabio Marongiu, Edward J. Evans, David A. Moore, Felipe S. Rodrigues, Oriol Pich, Bjorn Bakker, Hongui Cha, Renelle Myers, Febe van Maldegem, Jesse Boumelha, Selvaraju Veeriah, Andrew Rowan, Cristina Naceur-Lombardelli, Takahiro Karasaki, Monica Sivakumar, Swapnanil De, Deborah R. Caswell, Ai Nagano, James R. M. Black, Carlos Martinez-Ruiz, Min Hyung Ryu, Ryan D. Huff, Shijia Li, Marie-Julie Fave, Alastair Magness, Alejandro Suarez-Bonnet, Simon L. Priestnall, Margreet Luechtenborg, Katrina Lavelle, Joanna Pethick, Steven Hardy, Fiona E. McRonald, Meng-Hung Lin, Clara I. Troccoli, Moumita Ghosh, York E. Miller, Daniel T. Merrick, Robert L. Keith, Maise Al Bakir, Chris Bailey, Mark S. Hill, Lao H. Saal, Yilun Chen, Anthony M. George, Christopher Abbosh, Nnennaya Kanu, Se-Hoon Lee, Nicholas McGranahan, Christine D. Berg, Peter Sasieni, Richard Houlston, Clare Turnbull, Stephen Lam, Philip Awadalla, Eva Groenroos, Julian Downward, Tyler Jacks, Christopher Carlsten, Ilaria Malanchi, Allan Hackshaw, Kevin Litchfield, Jason F. Lester, James DeGregori, Mariam Jamal-Hanjani, Charles Swanton
Summary: This study reveals a strong association between PM2.5 air pollutants and lung cancer risk, suggesting that these pollutants promote lung cancer development by acting on cells with pre-existing oncogenic mutations in healthy lung tissue. The mechanism involves the influx of macrophages and release of interleukin-1 beta, which induce a progenitor-like state in EGFR mutant lung alveolar type II epithelial cells, fueling tumorigenesis. The findings underscore the tumor-promoting role of PM2.5 air pollutants and emphasize the need for public health policy initiatives to address air pollution.
Correction
Oncology
Emma Nolan, Victoria Louise Bridgeman, Luigi Ombrato, Adam Karoutas, Nicolas Rabas, Celine Angeli Natascha Sewnath, Marcos Vasquez, Felipe Silva Rodrigues, Stuart Horswell, Peter Faull, Rebecca Carter, Ilaria Malanchi