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the Mirati drug, called adagrasib, shrank tumors in 43% of patients with advanced lung cancer

With new data on its KRAS-blocking lung cancer drug, Mirati expects to take on a rival Amgen treatment

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

Source : https://www.statnews.com/2022/05/26/with-new-data-on-its-kras-blocking-lung-cancer-drug-mirati-expects-to-take-on-a-rival-amgen-treatment/

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Correlation of KRAS G12C Mutation and High PD-L1 Expression with Clinical Outcome in NSCLC Patients Treated with Anti-PD1 Immunotherapy - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35329953/


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...

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KRAS mutation allele frequency threshold alters prognosis in right-sided resected pancreatic cancer - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35333412/


Conclusion: This study demonstrates the importance of KRAS mutant allele frequency on pathological characteristics and prognosis in right-sided PDAC treated with surgery.

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Molecular characterization of KRAS wild type tumors in patients with pancreatic adenocarcinoma - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35302596/


Conclusions: KRAS-WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS-WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.

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KRAS and NRAS mutational analysis in plasma ctDNA from patients with metastatic colorectal cancer by real-time PCR and digital PCR - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35303157/


Conclusions: 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, while being cheaper and much less labor-intensive, for the detection of RAS mutations in plasma, either at diagnosis or after...

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BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers - Journal of Hematology & Oncology

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

Source : https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01241-3


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...

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Direct Targeting KRAS Mutation in Non-Small Cell Lung Cancer: Focus on Resistance - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35267628/


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...

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A prognostic classification based on the International Association for the Study of Lung Cancer histologic grading and immunoscore in KRAS-mutant invasive non-mucinous adenocarcinoma - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35246953/


Conclusions:The Grading-Immunoscore classification refines the prognostic grouping of histological grading and might aid in the screening of potential candidates for immunotherapy in patients with KRAS-mutant adenocarcinoma.

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PP6 deficiency in mice with KRAS mutation and Trp53 loss promotes early death by PDAC with cachexia-like features - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35247012/


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...

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targeted treatment options for the KRAS G12C mutation now approved in the UK

Revolutionary 'Death Star' Targeting Lung Cancer Drug Available on the NHS

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

Source : https://www.medscape.com/viewarticle/969575

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Development and validation of a robust and sensitive HPLC-MS/MS method for the quantitation of MRTX849 in plasma and its application in pharmacokinetics

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

Source : https://pubs.rsc.org/en/content/articlelanding/2022/AN/D1AN01928G


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...

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ABCB1 limits brain exposure of the KRAS G12C inhibitor sotorasib, whereas ABCB1, CYP3A, and possibly OATP1a/1b restrict its oral availability - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35192958/


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.

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Concomitant KRAS mutations attenuate sensitivity of non-small cell lung cancer cells to KRAS G12C inhibition - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35177674/


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...

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Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates

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

Source : https://www.frontiersin.org/articles/10.3389/fimmu.2021.786069/full


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...

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This final decision expands eligibility for people with Medicare to get lung cancer screening with LCDT by lowering the starting age for screening from 55 to 50 years and reducing the tobacco smoking history from at least 30 packs per year to at least 20 packs per year.

CMS Expands Coverage of Lung Cancer Screening with Low Dose Computed Tomography | CMS

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

Source : https://www.cms.gov/newsroom/press-releases/cms-expands-coverage-lung-cancer-screening-low-dose-computed-tomography

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The FDA is reviewing Mirati's KRAS-blocking lung cancer drug - but taking longer to do it

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

Source : https://www.statnews.com/2022/02/15/fda-mirati-kras-lung-cancer/

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Resistance to mutant KRAS V12-induced senescence in a hTERT/Cdk4-immortalized normal human bronchial epithelial cell line - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35149086/


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...

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Targeting KRAS in Lung Cancer Beyond KRAS G12C Inhibitors: The Immune Regulatory Role of KRAS and Novel Therapeutic Strategies - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35096591/


Relevance: We aim to summarize the tumor heterogeneity of KRAS mutant lung cancers and its immune-regulatory role, to report the efficacy achieved with current immunotherapies, and to overview the therapeutic approaches targeting KRAS mutations besides KRAS G12C inhibitors.

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Targeting RAS oncogenesis with SOS1 inhibitors - PubMed

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

Source : https://pubmed.ncbi.nlm.nih.gov/35101230/


Relevance: We summarize the current understanding of which combination partners may be most beneficial for patients with RAS driven tumors.

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Not all RAS mutations are equal: A detailed review of the functional diversity of RAS hot spot mutations

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

Source : https://www.sciencedirect.com/science/article/abs/pii/S0065230X2100066X?via=ihub


Relevance: Continuing to examine the biochemical differences in each RAS-mutant protein will continue to provide additional breakthroughs in allele-specific therapeutic strategies.