Article
Oncology
Yumi Oh, Hae Rim Jung, Seoyeon Min, Jinjoo Kang, Dongjun Jang, Seungjae Shin, Jiwon Kim, Sang Eun Lee, Chang Ohk Sung, Won-Suk Lee, Charles Lee, Eui Man Jeong, Sung-Yup Cho
Summary: Cancer chemotherapeutic drugs that target BCL-X-L can increase intracellular ROS levels in KRAS-mutant colorectal cancer cells, and exhibit a synergistic effect with the superoxide dismutase inhibitor 2-ME by regulating the translation of the anti-apoptotic protein MCL1.
Article
Chemistry, Medicinal
Chaofan Wang, Jie Li, Lingzhi Qu, Xia Tang, Xiaojuan Song, Fang Yang, Xiaojuan Chen, Qianmeng Lin, Weibin Lin, Yang Zhou, ZhengChao Tu, Yongheng Chen, Zhang Zhang, Xiaoyun Lu
Summary: MET alterations are crucial in NSCLC and gastric cancers. We designed and optimized a series of new c-Met inhibitors using molecular hybridization and macrocyclization strategy, among which D6808 exhibited potent inhibitory activity, extraordinary target specificity, and promise for further anticancer drug development.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Oncology
Victor Hugo Fonseca de Jesus, Maria Cecilia Mathias-Machado, Joao Paulo Fogacci de Farias, Marcelo Porfirio Sunagua Aruquipa, Alexandre A. Jacome, Renata D'Alpino Peixoto
Summary: Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with poor prognosis. The discovery of KRAS mutations as a pivotal event in pancreatic carcinogenesis has opened new avenues for targeted therapy. Recent research has provided insights into the different KRAS mutations, their prognostic implications, and therapeutic opportunities. Inhibitors of KRAS signaling, particularly KRAS G12C inhibitors, have shown promise in clinical trials. Overall, understanding the role of KRAS in PDAC offers hope for a significant improvement in treatment outcomes.
Article
Oncology
Lauren Schmalz, Chance Bloomer, Wei Zhang, William Petty
Summary: Targeted therapies have greatly improved the treatment outcomes for metastatic non-small cell lung cancer with oncogenic driver mutations. However, managing concurrent mutations and overcoming resistance remain challenging. This case demonstrates the utility of longitudinal next-generation sequencing testing in identifying acquired resistance and the effectiveness of amivantamab in achieving a durable treatment response.
Article
Multidisciplinary Sciences
Qiming Zhou, Yao Peng, Fenfen Ji, Huarong Chen, Wei Kang, Lam-Shing Chan, Hongyan Gou, Yufeng Lin, Pingmei Huang, Danyu Chen, Qinyao Wei, Hao Su, Cong Liang, Xiang Zhang, Jun Yu, Chi Chun Wong
Summary: SLC25A22 knockout reverts KRAS-mediated immunosuppression in CRC models by suppressing CXCL1 production and impairing MDSC recruitment. Mechanistically, SLC25A22 promotes asparagine-mediated SRC phosphorylation, which drives CXCL1 transcription and MDSC infiltration. Targeting SLC25A22 in combination with anti-PD1 therapy shows promising results in inhibiting MDSC and activating CD8(+) T cells to suppress KRAS-mutant CRC growth.
NATURE COMMUNICATIONS
(2023)
Review
Oncology
Valeria Merz, Marina Gaule, Camilla Zecchetto, Alessandro Cavaliere, Simona Casalino, Camilla Pesoni, Serena Contarelli, Fabio Sabbadini, Monica Bertolini, Domenico Mangiameli, Michele Milella, Vita Fedele, Davide Melisi
Summary: Mutations in the KRAS proto-oncogene are frequently found in cancer, with the G12C variant being particularly actionable in non-small cell lung cancer. Clinical trials of KRAS inhibitors are ongoing, along with exploration of alternative approaches targeting the KRAS pathway.
FRONTIERS IN ONCOLOGY
(2021)
Article
Oncology
Li Liu, Farhin Shaheed Kalyani, Haiyan Yang, Chunhua Zhou, Yi Xiong, Songlin Zhu, Nong Yang, Jingjing Qu
Summary: MET amplification or METex14 skipping mutations are rare oncogenic events in NSCLC patients. Treatment with MET TKIs may lead to shorter progression-free survival in patients with MET amplification compared to those with METex14 skipping mutations. Concurrent mutations could also impact the efficacy of MET TKIs in these patients.
FRONTIERS IN ONCOLOGY
(2021)
Article
Medicine, General & Internal
Wei Wu, Yu Liu, Yuzhi Jin, Lulu Liu, Yixuan Guo, Mian Xu, Qing Hao, Dazhi Li, Weijia Fang, Aibin Zhang, Peng Zhao
Summary: This article reports a case of a female pancreatic cancer patient. By utilizing next-generation sequencing, potential therapeutic targets for pancreatic cancer were identified, and corresponding drug treatments were administered, resulting in disease stabilization.
FRONTIERS IN MEDICINE
(2022)
Article
Oncology
Judy Wang, Patricia Martin-Romano, Philippe Cassier, Melissa Johnson, Eric Haura, Laurie Lenox, Yue Guo, Nibedita Bandyopadhyay, Michael Russell, Elizabeth Shearin, Josh Lauring, Laetitia Dahan
Summary: This study investigated the use of the oral inhibitor JNJ-74699157, targeting the KRAS G12C mutation, in advanced cancer patients. Dose escalation led to dose-limiting toxicities of increased blood CPK and no significant clinical benefit was observed. Further enrollment was stopped due to these findings.
Review
Oncology
Mara N. Zeissig, Lauren M. Ashwood, Olga Kondrashova, Kate D. Sutherland
Summary: KRAS is the most frequently mutated oncogene in cancer, with G12D mutation having the highest prevalence across various cancers and adenocarcinomas. Understanding the biology of KRAS-G12D cancers and identifying biomarkers for therapeutic response prediction is crucial for developing effective treatment strategies.
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
Oncology
Shinichiro Suzuki, Kimio Yonesaka, Takeshi Teramura, Toshiyuki Takehara, Ryoji Kato, Hitomi Sakai, Koji Haratani, Junko Tanizaki, Hisato Kawakami, Hidetoshi Hayashi, Kazuko Sakai, Kazuto Nishio, Kazuhiko Nakagawa
Summary: The study identified MET amplification as a mechanism of resistance to KRAS(G12C) inhibitors in NSCLC. Using MET inhibitor Crizotinib restored sensitivity to sotorasib, and dual inhibition of MET and KRAS(G12C) led to tumor shrinkage in sotorasib-resistant xenograft mice.
CLINICAL CANCER RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Hidayati Husainy Hasbullah, Marahaini Musa
Summary: Colorectal cancer is the third most commonly diagnosed malignancy globally, with most cases still being diagnosed at advanced stages despite efforts to raise awareness and advancements in treatment. Gene therapy targeting defect genes like TP53 and KRAS shows potential as an alternative treatment avenue for CRC, but faces limitations such as lack of related technology, high cost, and ethical issues.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Tong Xu, Mathijs Verhagen, Rosalie Joosten, Wenjie Sun, Andrea Sacchetti, Leonel Munoz Sagredo, Veronique Orian-Rousseau, Riccardo Fodde
Summary: Phenotypic plasticity plays a crucial role in allowing carcinoma cells to acquire transient mesenchymal features for invasion and metastasis. Epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions are regulated by a broad range of epigenetic mechanisms, including alternative splicing (AS). In this study, we focus on the role of AS in eliciting phenotypic plasticity in colon cancer and identify specific RNA-binding proteins (RBPs) that alter AS patterns, leading to the generation of splicing isoforms associated with increased invasion and metastasis. Further validation studies show that these RBPs and splicing isoforms promote local invasion and distant metastasis in colon cancer and are associated with poor survival.
Article
Oncology
Chenyue Zhang, Kai Wang, Jiamao Lin, Haiyong Wang
Summary: This study explored the association between TP53 mutation and atezolizumab in non-small-cell lung cancer (NSCLC) patients. It was found that NSCLC patients with TP53/KRAS co-mutation had longer overall survival (OS) with atezolizumab compared to docetaxel. However, there was no significant difference in OS between atezolizumab and docetaxel for NSCLC patients with only TP53 mutation or KRAS mutation.
