Review
Oncology
Lilith Trassl, Georgios T. Stathopoulos
Summary: Malignant pleural mesothelioma (MPM) is a rare and incurable cancer, mainly caused by asbestos inhalation. Previous studies have underestimated the frequency of KRAS pathway alterations in MPM, but recent research has identified KRAS mutations and copy number alterations in a significant proportion of MPM patients.
Article
Oncology
Katherine Priest, Anh Le, Amanuail Gebregzabheir, Hala Nijmeh, Gregory B. B. Reis, Melanie Mandell, Kurtis D. D. Davies, Carolyn Lawrence, Emily O'Donnell, Robert C. C. Doebele, Liming Bao, Dara L. L. Aisner, Erin L. L. Schenk
Summary: Patients with metastatic NSCLC bearing a ROS1 gene fusion often have prolonged disease control with ROS1-targeting TKIs, but heterogeneity due to co-occurring genomic alterations exists. This report describes a patient with metastatic NSCLC having a concurrent ROS1 fusion and KRAS p.G12C mutation, who had limited response to entrectinib, a ROS1 TKI. The patient was subsequently treated with sotorasib, a KRAS p.G12C inhibitor, which demonstrated improved response in a patient-derived cell line. The case highlights the importance of broad molecular profiling in metastatic NSCLC for both therapeutic and prognostic implications.
NPJ PRECISION ONCOLOGY
(2023)
Review
Oncology
Lisa Maria Mustachio, Anca Chelariu-Raicu, Lorant Szekvolgyi, Jason Roszik
Summary: KRAS, mutated in 25% of human cancers, is crucial for tumorigenesis. Despite difficulties in directly targeting it, success has been found in targeting other proteins in the RAS pathway. Recent findings suggest progress towards developing a direct KRAS inhibitor, highlighting the need for continued research for an optimal treatment for certain tumor types.
Review
Oncology
Narendra Wajapeyee, Romi Gupta
Summary: Cancer cells harbor multiple genetic and epigenetic alterations, but targeted therapy can still effectively treat various types of cancer. Resistance often emerges, posing a major clinical hurdle. Mechanisms for resistance to targeted therapy have been identified through alterations to the transcriptome and chromatin regulatory proteins.
Article
Biochemistry & Molecular Biology
Hannah R. Warren, Sarah J. Ross, Paul D. Smith, Judy M. Coulson, Ian A. Prior
Summary: Research on emerging resistance to different classes of Ras targeted therapies revealed rapid reactivation of Ras signaling and continued adaptive responses. Despite distinct gene signatures, commonly up-regulated upstream nodes promoting Ras activation were identified. Experiments to reverse resistance showed frequent desensitization to anti-cancer therapeutics, while triple inhibitor combinations showed more durable responses.
BIOCHEMICAL JOURNAL
(2022)
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)
Article
Medicine, Research & Experimental
M. Janusz Mezynski, Angela M. Farrelly, Mattia Cremona, Aoife Carr, Clare Morgan, Julie Workman, Paul Armstrong, Jennifer McAuley, Stephen Madden, Joanna Fay, Katherine M. Sheehan, Elaine W. Kay, Ciara Holohan, Yasir Elamin, Shereen Rafee, Patrick G. Morris, Oscar Breathnach, Liam Grogan, Bryan T. Hennessy, Sinead Toomey
Summary: Aberrant PI3K signaling is related to trastuzumab resistance in HER2-positive gastric cancer. PIK3CA mutations were only found in HER2-negative tumors, while ERBB-family mutations were identified in both HER2-positive and HER2-negative tumors. Copanlisib showed anti-proliferative effects in 4/5 cell lines, and combination with anti-HER2 therapy significantly improved growth inhibition in HER2-positive GC cells.
JOURNAL OF TRANSLATIONAL MEDICINE
(2021)
Article
Oncology
Nagla Abdel Karim, Asad Ullah, Peterson Pathrose, Hassana Fathallah, Ashley Perry, John C. Morris, Jiang Wang, Sandra L. Starnes
Summary: This study found that there is an increased expression of ERCC1, TS, and SRC in KRAS-mutant non-small cell lung cancer (NSCLC) patients. BRCA1 expression is higher in wild-type KRAS tumors, while SRC expression is decreased in mutant KRAS tumors. PD-L1 expression is lower in mutant KRAS tumors. Mutant KRAS tumors are resistant to platinum, taxane, and pemetrexed, while wild-type KRAS tumors with BRCA1 positivity may be sensitive to taxane therapy.
Review
Chemistry, Medicinal
Corrado Pelaia, Alessandro Vatrella, Luca Gallelli, Nicola Lombardo, Angela Sciacqua, Rocco Savino, Girolamo Pelaia
Summary: The p38 MAPK subgroup plays a crucial role in the pathogenesis of asthma and COPD by regulating the expression of various inflammatory mediators and fibrogenic factors. Studies suggest that p38 MAPK may be a potential therapeutic target, with research evaluating its effects in both asthma and COPD treatment.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2021)
Review
Endocrinology & Metabolism
Katharina Wang, Joakim Crona, Felix Beuschlein, Ashley B. Grossman, Karel Pacak, Svenja Noelting
Summary: Molecular targeted therapy plays an important role in the treatment of metastatic pheochromocytomas and paragangliomas. Some therapies are already in use with promising results, while others are still under evaluation in clinical trials. The development of molecular targeted therapies is of great significance for future tumor treatment.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2022)
Review
Cell Biology
Ravi Salgia, Rebecca Pharaon, Isa Mambetsariev, Arin Nam, Martin Sattler
Summary: KRAS, a common driver in solid tumors such as NSCLC, was initially considered undruggable due to lack of specific small-molecule inhibitors. However, with a better understanding of its transformation mechanisms and the development of immunological approaches targeting KRAS neoantigens, a race for approved therapies has emerged for KRAS mutant NSCLC patients.
CELL REPORTS MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Zhiwei Liu, Yingluo Liu, Lili Qian, Shangwen Jiang, Xiameng Gai, Shu Ye, Yuehong Chen, Xiaomin Wang, Linhui Zhai, Jun Xu, Congying Pu, Jing Li, Fuchu He, Min Huang, Minjia Tan
Summary: This study provides a comprehensive profile of the proteome and phosphoproteome of KRAS mutant cancer cell lines, identifying three subsets with distinct characteristics and a set of drug combinations with therapeutic potentials. The integration of phosphoproteome and drug sensitivity information facilitates the identification of effective treatments specific for certain subsets of KRAS mutant cancers.
Review
Oncology
Sahar F. Bannoura, Husain Yar Khan, Asfar S. Azmi
Summary: KRAS mutations are common in cancer, and recent advancements have shown that small molecule inhibitors can be developed against KRAS G12C, although there is still no agent to target KRAS G12D. However, significant progress has been made in developing compounds that can bind to and inhibit KRAS G12D, including MRTX1133. Additionally, an immunotherapeutic approach using adoptive T-cell transfer has shown promise in targeting G12D in pancreatic cancer.
FRONTIERS IN ONCOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Francesco Bruno, Alessia Pellerino, Luca Bertero, Riccardo Soffietti, Roberta Ruda
Summary: This article reviews recent progress in the molecular understanding of and therapeutic options for rare brain tumors in both children and adults, showing how specific molecular treatments can improve neurological symptoms and quality of life.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Marie Fernandes, Philippe Jamme, Alexis B. Cortot, Zoulika Kherrouche, David Tulasne
Summary: Although targeted therapies have extended the life expectancy of patients with druggable molecular alterations directly involved in tumor development, the emergence of acquired resistances limits their efficacy, leading to treatment failure. Recent studies have shown that activation of the MET receptor can promote resistance to various targeted therapies, highlighting MET as a key player in resistance mechanisms.