Molecular Bases for Combinatorial Treatment Strategies in Patients with KRAS Mutant Lung Adenocarcinoma and Squamous Cell Lung Carcinoma

Lazzari, Chiara; Verlicchi, Alberto; Gkountakos, Anastasios; Pilotto, Sara; Santarpía, Mariacarmela; Chaib, Imane; Serrano, J.; Viteri, Santiago; Morales-Espinosa, Daniela; Dazzi, Claudio; Marinis, Filippo de; Cao, Peng; Karachaliou, Niki; Rosell, Rafael

doi:10.1007/s41030-016-0013-3

Cited by 3 publications

(4 citation statements)

References 106 publications

(74 reference statements)

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“…Binding of Cdc42/Rac1 to Cdc42/Rac1-binding domain (CRIB) relieves inhibition by disrupting the PAK1 homodimer [28]. PAK1 is activated by several mechanisms that include PKCι commonly upregulated in NSCLC [12, 29], such as TNFα, CD3/CD28 (T cell receptor engagement). EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is tempting to speculate that an EGFR TKI, PAK inhibitor combination could serve as novel combinatory therapy for EGFR mutant NSCLC. The development of PAK1 inhibitors is difficult due to their large and highly flexible catalytic pocket and highly mobile N-terminal lobe [29, 31, 32]. PAK inhibitor combinations with targeted drugs have been tested in NSCLC cell lines, including apoptosis protein inhibitors (IAP, EGFR, MEK1/2 and Src inhibitors with PAK1 knockdown) [33].…”

Section: Discussionmentioning

confidence: 99%

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Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Ito

Codony-Servat

et al. 2019

Cell Commun Signal

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Introductionp21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models.MethodsThe effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models.ResultsThe combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment.ConclusionsCombination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Ito

Codony-Servat

et al. 2019

Cell Commun Signal

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“…Therapeutic strategies to block EGFR include monoclonal antibodies and receptor tyrosine kinase inhibitors. Monoclonal antibodies (e.g., necitumumab, matuzumab, panitumumab) target the extracellular domain of EGFR [ 224 ], while small molecules inhibitors (e.g., gefitinib, erlotinib) target the tyrosine kinase activity of EGFR [ 225 , 226 ]. However, despite the prevalence of EGFR mutations in NSCLC, many patients are refractory to EGFR-targeted therapies [ 227 ].…”

Section: Stat3 As a Therapeutic Targetmentioning

confidence: 99%

Multicellular Effects of STAT3 in Non-small Cell Lung Cancer: Mechanistic Insights and Therapeutic Opportunities

Parakh

Ernst

Poh

2021

Cancers

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Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 85% of lung cancer cases. Aberrant activation of the Signal Transducer and Activator of Transcription 3 (STAT3) is frequently observed in NSCLC and is associated with a poor prognosis. Pre-clinical studies have revealed an unequivocal role for tumor cell-intrinsic and extrinsic STAT3 signaling in NSCLC by promoting angiogenesis, cell survival, cancer cell stemness, drug resistance, and evasion of anti-tumor immunity. Several STAT3-targeting strategies have also been investigated in pre-clinical models, and include preventing upstream receptor/ligand interactions, promoting the degradation of STAT3 mRNA, and interfering with STAT3 DNA binding. In this review, we discuss the molecular and immunological mechanisms by which persistent STAT3 activation promotes NSCLC development, and the utility of STAT3 as a prognostic and predictive biomarker in NSCLC. We also provide a comprehensive update of STAT3-targeting therapies that are currently undergoing clinical evaluation, and discuss the challenges associated with these treatment modalities in human patients.

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“…The fact that activation of YAP1 stimulates secretion of FGF ligands and expression of FGFR in ovarian cancer is significant (15). Different lines of evidence show that, following MEK inhibition, there could be overexpression of other RTKs, like MET and AXL, as well as overactivation of Src-YAP1-NOTCH-HES1, in addition to STAT3 (16,17). AXL overexpression has been a trait of KRAS mutant cell lines with mesenchymal features responding to the combination of erlotinib and an AXL inhibitor (18), or the combination of the AXL inhibitor, TP0903, plus a PARP inhibitor (olaparib) (19).…”

Section: Inhibition Of Mek a Canonical Kras Pathway Effector In Kras Mutant Nsclcmentioning

confidence: 99%

Inhibition of MEK, a canonical KRAS pathway effector in KRAS mutant NSCLC

Rosell

Karachaliou²,

Codony-Servat³

et al. 2018

Transl. Lung Cancer Res.

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Molecular Bases for Combinatorial Treatment Strategies in Patients with KRAS Mutant Lung Adenocarcinoma and Squamous Cell Lung Carcinoma

Cited by 3 publications

References 106 publications

Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Multicellular Effects of STAT3 in Non-small Cell Lung Cancer: Mechanistic Insights and Therapeutic Opportunities

Inhibition of MEK, a canonical KRAS pathway effector in KRAS mutant NSCLC

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