The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC)

Salgia, Ravi; Pharaon, Rebecca; Mambetsariev, Isa; Nam, Arin; Sattler, Martin

doi:10.1016/j.xcrm.2020.100186

Cited by 109 publications

(92 citation statements)

References 131 publications

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“…A major argument for multiple gene testing using DNAand RNA-based NGS is the rapidly evolving landscape of targetable alterations in NSCLC. KRAS mutations, for example, have long been regarded as strictly undruggable and are now in the spotlight of drug development (29). Especially drugs targeting the KRAS G12C mutation (e.g., Sotrasib and Adagrasib) show promising data in clinical trials (30,31).…”

Section: Discussionmentioning

confidence: 99%

Reflex testing in non-small cell lung carcinoma using DNA- and RNA-based next-generation sequencing—a single-center experience

Zacharias¹,

Absenger²,

Kashofer³

et al. 2021

Transl Lung Cancer Res

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Section: Discussionmentioning

confidence: 99%

Reflex testing in non-small cell lung carcinoma using DNA- and RNA-based next-generation sequencing—a single-center experience

Zacharias¹,

Absenger²,

Kashofer³

et al. 2021

Transl Lung Cancer Res

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“…Sotorasib (AMG-510) is a selective and irreversible KRAS G12C inhibitor that restrains KRAS in the inactive GDP-bound state. The effects of specific KRAS inhibitors, such as AMG-510 and MRTX849 targeting specific G12C mutations (KRAS G12C ) are being investigated in ongoing clinical trials in non-small cell lung cancer [ 136 ]. In a clinical trial study evaluating the effect of sotorasib, patients with lung cancer exhibited a better tumor response than did patients with CRC [ 137 ].…”

Section: Potential Therapeutic Targeting Of Ereg/egfr and Alternative Pathwaysmentioning

confidence: 99%

The Role of EREG/EGFR Pathway in Tumor Progression

Cheng

Feng

Lee

et al. 2021

IJMS

109

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Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.

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“…Therapies directed at HER2 mutations are also emerging, and testing for KRAS mutations would be beneficial [1][2][3]. The FDA recently approved a therapy directed at KRAS G12C mutations [55], and several more inhibitors of KRAS-regulated pathways and specific inhibitors against KRAS G12C mutations are in development [56,57].…”

Section: Biomarkersmentioning

confidence: 99%

Molecular testing in stage I–III non-small cell lung cancer: Approaches and challenges

et al. 2021

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The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC)

Cited by 109 publications

References 131 publications

Reflex testing in non-small cell lung carcinoma using DNA- and RNA-based next-generation sequencing—a single-center experience

Reflex testing in non-small cell lung carcinoma using DNA- and RNA-based next-generation sequencing—a single-center experience

The Role of EREG/EGFR Pathway in Tumor Progression

Molecular testing in stage I–III non-small cell lung cancer: Approaches and challenges

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