s Mirati Therapeutics waits for the Food and Drug Administration to complete a review of its KRAS-targeting lung cancer drug later this year, final results from a clinical trial reported ..... see more
Given the limitations due to the small sample size and exploratory nature of this study, we tentatively conclude the KRAS G12C mutation should be considered in future trials as a ..... see more
Conclusions: Given the limitations due to the small sample size and exploratory nature of this study, we tentatively conclude the KRAS G12C mutation should be considered in future trials as a predictive marker of prolonged response to first-line ICIs in NSCLC patients overexpressing PD-L1. This finding could be relevant as anti-KRAS G12C...
doi: 10.1002/jso.26860. Online ahead of print. 1 Department of Surgery, Jefferson Pancreas, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Background: Next-generation sequencing (NGS) provides information on ..... see more
doi: 10.1158/1078-0432.CCR-21-3581. Online ahead of print. 1 Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, mi, United States. 2 Karmanos Cancer Institute, Detroit, United States. 3 Caris Life ..... see more
Analysis of ctDNA is a viable strategy for clinical management of mCRC patients. Although the OncoBEAM assay sensitivity is somewhat higher, the fully automated Idylla platform also has good performance, ..... see more
KRAS mutations are the most common oncogenic drivers. Sotorasib (AMG510), a covalent inhibitor of KRASG12C, was recently approved for the treatment of KRASG12C-mutated non-small cell lung cancer (NSCLC). However, the ..... see more
Conclusion/Relevance: We observed heterogeneous responses to sotorasib alone, whereas its combination with DT2216 strongly inhibited viability of KRASG12C tumor cell lines that partially responded to sotorasib treatment. Mechanistically, sotorasib treatment led to stabilization of BIM and co-treatment with DT2216 inhibited sotorasib-induced...
KRAS is the most frequently mutated oncogene in non-small cell lung cancers (NSCLC), with a frequency of around 30%, and encoding a GTPAse that cycles between active form (GTP-bound) to ..... see more
Conclusion/Relevance: Small molecules such as sotorasib are now the first targeted drugs for KRAS G12C mutation, preventing conversion of the mutant protein to GTP-bound active state. Little is known about primary or acquired resistance. Acquired resistance does occur and may be due to genetic alterations in the nucleotide exchange function or...
doi: 10.1111/1759-7714.14360. Online ahead of print. 1 Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China. 2 Department ..... see more
doi: 10.1111/cas.15315. Online ahead of print. 1 Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan. 2 Division of Cancer Molecular Biology, Tohoku University Graduate School of Medicine, ..... see more
Conclusion: Overall, Ppp6c deficiency in the presence of K-ras mutations and Trp53 gene deficiency promoted pancreatic tumorigenesis with generalized cachexia and early death. This study is the first evidence that Ppp6c suppresses mouse pancreatic carcinogenesis and supports use of Ppp6c-deficient cKP mice as a model for developing treatments...
A revolutionary life-extending drug has received approval from the National Institute for Health and Care Excellence (NICE) making it available on the NHS for patients with lung cancer. Following an ..... see more
MRTX849 is a novel, highly selective, targeted inhibitor of KRAS (G12C), which significantly improves the objective response rate in patients with advanced solid tumors. However, neither an analytical HPLC-MS/MS assay ..... see more
Relevance: MRTX849 is a novel, highly selective, targeted inhibitor of KRAS (G12C), which significantly improves the objective response rate in patients with advanced solid tumors. However, neither an analytical HPLC-MS/MS assay nor pharmacokinetics has been reported for MRTX849 in plasma. In the present study, chromatography was accomplished...
Sotorasib (Lumakras TM ) is the first FDA-approved KRAS G12C inhibitor for treatment of patients with non-small cell lung cancer (NSCLC) carrying this mutation. Using genetically modified mouse models, we ..... see more
Conclusion/Relevance: Collectively, the oral availability of sotorasib was markedly limited by CYP3A and possibly also by ABCB1 and OATP1a/b, whereas its brain accumulation was strongly restricted by ABCB1. The obtained results may help to further optimize the safety and efficacy of sotorasib in clinical use.
The development of covalent inhibitors against KRAS G12C represents a major milestone in treatment of RAS-driven cancers, especially in non-small cell lung cancer (NSCLC), where KRAS G12C is one of ..... see more
Relevance: Overall, our study provides a comprehensive assessment of co-occurring KRAS mutations in NSCLC and in vitro evidence of the negative impact of co-occurring KRAS mutations on cellular response to G12C inhibitors, highlighting the need for a comprehensive KRAS tumour genotyping for optimal patient selection for treatment with a KRAS...
Targeting K-RAS-mutant non-small cell lung cancer (NSCLC) with novel inhibitors has shown promising results with the recent approval of sotorasib in this indication. However, progression to this agent is expected, ..... see more
Conclusion/Relevance: By interrogating massive datasets, including TCGA, we identified genes that code for surface membrane proteins that are selectively expressed in K-RAS mutated NSCLC and that could be used to vectorize novel therapies. Two genes, CLDN10 and TMPRSS6, were selected for their clear differentiation. In addition, we discovered...
Today the Centers for Medicare & Medicaid Services (CMS) is announcing a national coverage determination (NCD) that expands coverage for lung cancer screening with low dose computed tomography (LDCT) to ..... see more
irati Therapeutics said Tuesday that U.S. regulators accepted an application for its KRAS-blocking lung cancer drug, but the review time will be longer than hoped. The Food and Drug Administration ..... see more
doi: 10.1016/j.yexcr.2022.113053. Online ahead of print. 1 Division of Host Defense Sciences, Dept. of Integrated Health Sciences, Nagoya University Graduate School of Medicine, Japan. 2 Division of Host Defense Sciences, ..... see more
Conclusion/Relevance: These results indicate that a hTERT/Cdk4 -immortalized normal bronchial epithelial cell line is partially resistant to mutant KRASV12-induced senescence. This suggests that OIS does not efficiently suppress KRASV12-induced transformation in the context of the simultaneous occurrence of telomerase upregulation and...
Approximately 20% of lung adenocarcinomas harbor KRAS mutations, an oncogene that drives tumorigenesis and has the ability to alter the immune system and the tumor immune microenvironment. While KRAS was ..... see more
RAS proteins play major roles in many human cancers, but programs to develop direct RAS inhibitors so far have only been successful for the oncogenic KRAS mutant G12C. As an ..... see more
The RAS family of small GTPases are among the most frequently mutated oncogenes in human cancer. Approximately 20% of cancers harbor a RAS mutation, and > 150 different missense mutations ..... see more