381MO Durability of clinical benefit and biomarkers in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib)

Hong, D.S.; Bang, Y-J.; Durm, Greg Andrew; Govindan, R.; Dy, Grace K.; Park, K.; Strickler, John H.; Burns, Timothy F.; Kim, J.; Ang, Agnes; Lipford, J. Russell; Ngarmchamnanrith, Gataree; Anderson, Abraham; Li, B.T.

doi:10.1016/j.annonc.2020.10.375

Cited by 3 publications

(4 citation statements)

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“…Such drugs will likely have lower toxicity than those targeting both wild-type and mutant protein. Many pharmaceutical companies are now developing more potent inhibitors of KRAS G12C ; some of these are entering clinical trials, while others remain in early development (Table 1) [11][12][13][14][15][77][78][79][80][81][82].…”

Section: Direct Inhibition Of Krasmentioning

confidence: 99%

“…However, subgroup sample sizes were small and future prospective studies are warranted. Clinical activity was also demonstrated across a range of mutational allele frequencies, PD-L1 expression levels, and tumor mutational burden (TMB) levels [13,77]. Finally, an analysis of patient-reported outcome measures from CodeBreaK 100 suggested that sotorasib maintained or improved quality of life, physical functioning, and the severity of key lung cancer-related symptoms [88].…”

Section: Sotorasibmentioning

confidence: 99%

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On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

et al. 2021

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Direct Inhibition Of Krasmentioning

confidence: 99%

Section: Sotorasibmentioning

confidence: 99%

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

et al. 2021

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“…An interesting report has shown that NSCLC patients treated with sotorasib, a KRAS G12C inhibitor, achieved disease control leading to a median progress free survival (PFS) of 6.9 months. However, this current limited dataset suggests that neither KRAS p.G12C MAF nor PD-L1 expression level predicts response to sotorasib [ 46 ]. Meanwhile, tumor therapy targeting m 6 A modification has attracted researchers’ attention.…”

Section: Discussionmentioning

confidence: 99%

YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation

Lou

Ning

Liu

et al. 2021

Cells

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KRAS and TP53 mutations are the two most common driver mutations in patients with lung adenocarcinoma (LUAD), and they appear to reduce latency and increase metastatic proclivity when a KRAS and TP53 co-mutation (KRAS/TP53-mut) occurs. However, the molecular mechanism involved is unclear. N6-methyladenosine (m6A), the most abundant RNA modification in mammal mRNAs, plays a critical role in tumorigenesis. Here, we used genomic and transcriptomic data and found that only LUAD patients with KRAS/TP53-mut, but not an individual mutation, appeared to exhibit poor overall survival when compared with patients without KRAS and TP53 mutation (wildtype). Subsequently, we analyzed the differential expression of the 15-m6A-related genes in LUAD with different mutations and found that YTHDF1 was the most upregulated in KRAS/TP53-mut patients and associated with their adverse prognosis. Bioinformatics and experimental evidence indicated that elevated YTHDF1 functionally promoted the translation of cyclin B1 mRNA in an m6A-dependent manner, thereby facilitating the tumor proliferation and poor prognosis of LUAD with KRAS/TP53-mut. Furthermore, the concurrent increase in YTHDF1 and cyclin B1 was confirmed by immunohistochemistry staining in patients with co-occurring KRAS/TP53 mutations. YTHDF1 was correlated with an unfavorable clinical stage and tumor size. Collectively, we identified and confirmed a novel “YTHDF1–m6A–cyclin B1 translation” axis as an essential molecular pathway for the prognosis of KRAS/TP53-mut LUAD.

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“…Furthermore, it has been demonstrated that cases with STK11 and TP53 co-occurring mutations responded better to sotorasib than patients harboring KEAP1 co-mutation [ 169 , 170 , 171 , 173 , 174 , 175 ]. Moreover, alterations in cell cycle effectors like in the WNT and MAPK pathways are more common in the late progressors group [ 176 ].…”

Section: Current Therapeutic Approaches and Perspectives In ...mentioning

confidence: 99%

Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers

Cekani

Epistolio

Dazio

et al. 2022

Cancers

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In non-small cell lung cancer (NSCLC) the most common alterations are identified in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, accounting for approximately 30% of cases in Caucasian patients. The majority of mutations are located in exon 2, with the c.34G > T (p.G12C) change being the most prevalent. The clinical relevance of KRAS mutations in NSCLC was not recognized until a few years ago. What is now emerging is a dual key role played by KRAS mutations in the management of NSCLC patients. First, recent data report that KRAS-mutant lung AC patients generally have poorer overall survival (OS). Second, a KRAS inhibitor specifically targeting the c.34G > T (p.G12C) variant, Sotorasib, has been approved by the U.S. Food and Drug Administration (FDA) and by the European Medicines Agency. Another KRAS inhibitor targeting c.34G > T (p.G12C), Adagrasib, is currently being reviewed by the FDA for accelerated approval. From the description of the biology of KRAS-mutant NSCLC, the present review will focus on the clinical aspects of KRAS mutations in NSCLC, in particular on the emerging efficacy data of Sotorasib and other KRAS inhibitors, including mechanisms of resistance. Finally, the interaction between KRAS mutations and immune checkpoint inhibitors will be discussed.

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381MO Durability of clinical benefit and biomarkers in patients (pts) with advanced non-small cell lung cancer (NSCLC) treated with AMG 510 (sotorasib)

Cited by 3 publications

References 0 publications

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

On target: Rational approaches to KRAS inhibition for treatment of non-small cell lung carcinoma

YTHDF1 Promotes Cyclin B1 Translation through m6A Modulation and Contributes to the Poor Prognosis of Lung Adenocarcinoma with KRAS/TP53 Co-Mutation

Molecular Biology and Therapeutic Perspectives for K-Ras Mutant Non-Small Cell Lung Cancers

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