Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies

Rizzolio, Sabrina; Cagnoni, Gabriella; Battistini, Chiara; Bonelli, Stefano; Isella, Claudio; Ginderachter, Jo A. Van; Bernards, René; Nicolantonio, Federica Di; Giordano, Silvia; Tamagnone, Luca

doi:10.1172/jci99257

Cited by 59 publications

(68 citation statements)

References 52 publications

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“…Moreover, the level of EGFR protein, which was medium in 21_TRAR cells and very high in 28_TRAR cells, reflected the extent of EGF dependence. Several mechanisms have been implicated in the regulation of EGFR expression including suppression of SOX10 [102,103] followed by upregulation of neuropilin-1 (NRP-1)-c-Jun N-terminal kinase (JNK)-SOX2 axis [106], and SOX9 expression [107]. It is unlikely that these mechanisms are involved in the regulation of EGFR in resistant cell lines investigated in our study as (i) changes in SOX9 and SOX10 expression were not uniformly correlated with EGFR protein level, (ii) EGF deprivation was associated with downregulation of SOX10 in EGFR high 28_TRAR cells suggesting even a concurrent regulation, and (iii) TRAR cells neither expressed SOX2 protein at the detectable level nor activated JNK as shown by the phospho-protein array.…”

Section: Discussionmentioning

confidence: 99%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line-and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKT high resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Hartman

Sztiller-Sikorska

Gajos-Michniewicz

et al. 2020

Cells

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“…Although many studies have revealed the importance of VEGF-NRP signaling in tumor cells, independently of its role in angiogenesis (5), its contribution to DNA repair mechanisms is significant. Of note, VEGF-NRP signaling has been implicated in drug resistance in multiple tumors, but satisfying mechanisms have been elusive (9,(48)(49)(50). Given that efficient HR is a key Fig.…”

Section: Discussionmentioning

confidence: 99%

The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression

Elaimy

Amante

Zhu

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF–NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF–NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF–NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ–TEAD transcriptional target. We also discovered that VEGF–NRP2–YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF–NRP2 or YAP/TAZ. These findings reveal roles for VEGF–NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF–NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.

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“…Broadly speaking we can distinguish mechanisms based on external and internal signals. For instance, RAF inhibitor resistant melanoma cells can upregulate the expression of neuropilin-1 (NRP1), which uses the JNK pathway to induce the expression of receptor tyrosine kinases (RTKs), specifically epidermal growth factor receptor (EGFR/ERBB1) and insulin-like growth factor receptor 1 (IGFR1), that can bypass the signaling block imposed by RAF inhibition [75]. The same mechanism applies in breast cancer cells treated with HER2 targeting drugs.…”

Section: Jnk Enhancing Resistance To Erk Pathway Inhibitors and Chemomentioning

confidence: 99%

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee

Rauch

Kölch

2020

IJMS

530

338

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Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

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Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies

Cited by 59 publications

References 52 publications

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

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