Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS mutant lung cancer

Padhye, Aparna; Konen, Jessica; Rodriguez, B. Leticia; Fradette, Jared J.; Ochieng, Joshua K.; Diao, Lixia; Wang, Jing; Lü, Wei; Solis, Luisa M.; Batra, Harsh Vardhan; Raso, Maria Gabriela; Peoples, Michael; Minelli, Rosalba; Carugo, Alessandro; Bristoe, Christopher; Gibbons, Don L.

doi:10.21203/rs.3.rs-355354/v1

Cited by 2 publications

(2 citation statements)

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“…These results indicated that KRT8 may exert its function by modulating cell migration and invasion in LUAD. Epithelial-to-mesenchymal transition (EMT) is a biologic phenomenon that can alter the state of cells along a phenotypic spectrum and cause transcriptional rewiring to produce distinct tumor cell subpopulations ( 25 ). It is reported that KRT8 can participate in cell migration and invasion through EMT ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMT via NF-κB Signaling

Chen

Pan

et al. 2022

Front. Oncol.

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Keratin 8 (KRT8) is the major component of the intermediate filament cytoskeleton and aberrant expression in multiple tumors. However, the role of KRT8 in lung adenocarcinoma (LUAD) remains unclear. In the present study, KRT8 expression was found to be upregulated along with prognosis and metastasis in LUAD. Kaplan–Meier analysis presented that the 5-year OS and DSS rates were significantly better among patients with low KRT8 expression compared to those with high expression. Correlation analysis showed that KRT8 expression was significantly associated with gender (P = 0.027), advanced T stage (P = 0.001), advanced N stage (P = 0.048), and advanced pathologic stage (P = 0.025). Univariate Cox analysis demonstrated that KRT8 was a predictor of OS [hazard ratio (HR) = 1.526; 95% confidence interval (CI) 1.141–2.040; P = 0.004] and DSS (HR = 1.625; 95% CI 1.123–2.353; P = 0.010) in the TCGA database. Importantly, downregulation of KRT8 obviously suppressed cell proliferation, cell migration, invasion, and EMT as well as induced cell apoptosis. KRT8 knockdown significantly inhibited NF-κB signaling, suggesting a potential mechanism. Overall, our results indicated that KRT8 could regulate lung carcinogenesis and may serve as a potential target for antineoplastic therapies.

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Section: Discussionmentioning

confidence: 99%

KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMT via NF-κB Signaling

Chen

Pan

et al. 2022

Front. Oncol.

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“…Regardless of inhibiting KRAS itself or the downstream MAPK pathway, EMT is blameworthy for drug resistance ( 45 ). Activation of the PI3K pathway in mesenchymal-like KRAS G12C mutant cancer cells could be the molecular basis for EMT-mediated resistance or, alternatively, could be due to a cell cycle alteration leading to CDK4-dependent growth ( 58 ). Cells expressing high levels of CSNK2A1 (Casein Kinase 2 Alpha 1) were found to have an increased mesenchymal gene signature, and reduction of CSNK2A1 converted the cells to the epithelial type and restored their sensitivity to KRAS G12C or MEK inhibitors ( 59 ).…”

Section: Non-genetic Adaptive Resistance Kras G12c ...mentioning

confidence: 99%

Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit

et al. 2022

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Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRASG12C inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRASG12C, such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRASG12C inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRASG12C-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRASG12C inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT.

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Targeting CDK4 overcomes EMT-mediated tumor heterogeneity and therapeutic resistance in KRAS mutant lung cancer

Cited by 2 publications

References 61 publications

KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMT via NF-κB Signaling

KRT8 Serves as a Novel Biomarker for LUAD and Promotes Metastasis and EMT via NF-κB Signaling

Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit

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