Evaluation of KRAS Concomitant Mutations in Advanced Lung Adenocarcinoma Patients

Aran, Veronica; Zalis, Mariano; Montella, T.; Sousa, Carlos Augusto Moreira de; Ferrari, Bruno; Ferreira, Carlos Gil

doi:10.3390/medicina57101039

Cited by 10 publications

(13 citation statements)

References 35 publications

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“…These biological diversities can be ascribed to the presence of co-occurring genetic events, to the co-presence of different KRAS gene mutation subtypes and to the mutant KRAS allelic content [ 87 ]. Although the role of KRAS co-occurring mutations remains to be elucidated, it has been described that they may affect treatment responses [ 88 ].…”

Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

“…KRAS mutations are mutually exclusive with alterations in other molecular markers such as EGFR , ALK and ROS1 , considered genetic drivers of lung cancer development. However, rare cases (<1%) harboring mutations in both KRAS and these markers have been reported [ 88 ]. In lung ACs, the rate of co-occurring mutations with KRAS alterations is 3.2%, and of the KRAS -mutant cases, 33% [ 88 , 89 ].…”

Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

“…However, rare cases (<1%) harboring mutations in both KRAS and these markers have been reported [ 88 ]. In lung ACs, the rate of co-occurring mutations with KRAS alterations is 3.2%, and of the KRAS -mutant cases, 33% [ 88 , 89 ]. These frequencies differ based on the specific KRAS mutation: c.34G > T (p.G12C) presents reportable co-mutations in 6.1% of lung ACs, c.35G > A (p.G12D) in 2.5% and c.35G > T (p.G12V) in 1.6% (including co-existing alterations with EGFR , BRAF and NRAS ) [ 87 , 88 ].…”

Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

“…In lung ACs, the rate of co-occurring mutations with KRAS alterations is 3.2%, and of the KRAS -mutant cases, 33% [ 88 , 89 ]. These frequencies differ based on the specific KRAS mutation: c.34G > T (p.G12C) presents reportable co-mutations in 6.1% of lung ACs, c.35G > A (p.G12D) in 2.5% and c.35G > T (p.G12V) in 1.6% (including co-existing alterations with EGFR , BRAF and NRAS ) [ 87 , 88 ]. The most frequent KRAS co-mutations were found in TP53 (42%), STK11 (29%) and Kelch-like ECH-associated protein 1 ( KEAP1 )/Nuclear factor erythroid 2-related factor 2 (NFE2L2) genes (27%) [ 90 ].…”

Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

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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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Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

Section: Kras and Co-occurring Mutations In Lung Acmentioning

confidence: 99%

See 2 more Smart Citations

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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“…The percentage of KRAS mutant alleles detected in the resistant tumours ranged from 0.4% to 17% [19]. Aside from that, KRAS mutations have been designated to be a driver mutation in cancer, with several publications demonstrating a low allelic frequency of KRAS concomitantly existing alongside other driver mutations such as EGFR [20,21], and it was found that de novo KRAS G12C mutation was present ranging from 0.2% [22] to 1.17% of detected samples (n = 6) [23,24]. Detecting de novo KRAS mutation requires high sensitivity and specificity technology, and it was found that KRAS mutation was absent using droplet digital PCR.…”

Section: Intrinsic Resistance In Krasmentioning

confidence: 99%

Delaying Emergence of Resistance to KRAS Inhibitors with Adaptive Therapy: “Treatment-to-Contain” Instead of “Treatment-to-Cure”

Hamdi¹,

Stanslas²

2022

Oncologie

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KRAS mutations are among the most common oncogenic abnormalities in cancer. Until recently, drug discovery pursuing KRAS did not produce therapeutic benefits for patients. Specific KRAS inhibitors, such as sotorasib and adagrasib, which bind covalently to codon 12 of substituted glycine to cysteine residue of the protein (G12C), have been approved by the FDA recently for the treatment of lung cancers. Binding of these drugs to the protein inhibits the activation of the GDP-bound inactive state to the GTP-bound active state. Phase 1/2 trials have shown potential anti-tumor activity, particularly in patients with previously treated non-small cell lung cancer. Acquired resistance, on the other hand, is inevitable, and the mechanisms include new KRAS mutations such as Y96D/C and other RAS-MAPK effector protein abnormalities. "Adaptive Therapy," an ecologically inspired concept, focuses on extending the treatment-free period in a treatment course to delay the emergence of resistance. This review focuses on acquired mechanisms of resistance to KRAS G12C inhibitors, as well as the application of adaptive therapy in the treatment of KRAS-mutated patients to maintain acquired resistance sub-clones and extend progression-free survival.

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Single‐cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation

Xu,

Ding,

Song

et al. 2024

The Journal of Gene Medicine

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BackgroundAberrant activation of the phosphatidlinositol 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway has been shown to play an important role in lung adenocarcinoma (LUAD). The effect of KRAS mutations, one of the important signatures of LUAD, on the PI3K/AKT/mTOR pathway in LUAD remains unclear.MethodsThe Seurat package and principal component analysis were used for cell categorization of single‐cell RNA sequencing data of LUAD. The AUCell score was used to assess the activity of the PI3K/AKT/mTOR pathway. Meanwhile, using the gene expression profiles and mutation profiles in the The Cancer Genome Atlas dataset, LUAD patients were categorized into KRAS‐mutant (KRAS‐MT) and KRAS‐wild‐types (KRAS‐WT), and the corresponding enrichment scores were calculated using gene set enrichment analysis analysis. Finally, the subpopulation of cells with the highest pathway activity was identified, the copy number variation profile of this subpopulation was inscribed using the inferCNV package and the CMap database was utilized to make predictions for drugs targeting this subpopulation.ResultsThere is higher PI3K/AKT/mTOR pathway activity in LUAD epithelial cells with KRAS mutations, and high expression of KRAS, PIK3CA, AKT1 and PDPK1. In particular, we found significantly higher levels of pathway activity and associated gene expression in KRAS‐MT than in KRAS‐WT. We identified the highest pathway activity on a subpopulation of GRB2+ epithelial cells and the presence of amplified genes within its pathway. Finally, drugs were able to target GRB2+ epithelial cell subpopulations, such as wortmannin, palbociclib and angiogenesis inhibitor.ConclusionsThe present study provides a basic theory for the activation of the PI3K/AKT/mTOR signaling pathway as a result of KRAS mutations.

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Evaluation of KRAS Concomitant Mutations in Advanced Lung Adenocarcinoma Patients

Cited by 10 publications

References 35 publications

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

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

Delaying Emergence of Resistance to KRAS Inhibitors with Adaptive Therapy: “Treatment-to-Contain” Instead of “Treatment-to-Cure”

Single‐cell RNA sequencing reveals the mechanism of PI3K/AKT/mTOR signaling pathway activation in lung adenocarcinoma by KRAS mutation

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