Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation

Sala, Margaux; Allain, Nathalie; Moreau, Mélanie; Jabouille, Arnaud; Henriet, Elodie; Abouhammoud, Aya; Uguen, Arnaud; Di-Tommaso, Sylvaine; Dourthe, Cyril; Raymond, Anne-Aurélie; Dupuy, Jean-William; Gérard, E.; Dugot‐Senant, Nathalie; Rousseau, Benoı̂t; Merlio, Jean-Philippe; Pham-Ledart, Anne; Vergier, Béatrice; Tartare‐Deckert, Sophie; Moreau, Violaine; Saltel, Frédéric

doi:10.1038/s41388-022-02266-1

Cited by 9 publications

(9 citation statements)

References 50 publications

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“…Interestingly, DDR2 targeting with the tyrosine kinase inhibitor dasatinib in combination with anti-PD-1 checkpoint inhibitor let to a better response than either single treatment 106 . In addition, DDR2 can modulate AXL expression 107 , while AXL inhibition induces type I interferon and expansion of TCF1 + CD8 + T cells 108 . Thus, amplification of DDR2 might indirectly lead to a worse response to ICI therapy by downregulating important immune features for response.…”

Section: Discussionmentioning

confidence: 99%

Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype

Hiltbrunner,

Cords,

Kasser

et al. 2023

Nat Commun

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Immune checkpoint inhibitor treatment has the potential to prolong survival in non-small cell lung cancer (NSCLC), however, some of the patients develop resistance following initial response. Here, we analyze the immune phenotype of matching tumor samples from a cohort of NSCLC patients showing good initial response to immune checkpoint inhibitors, followed by acquired resistance at later time points. By using imaging mass cytometry and whole exome and RNA sequencing, we detect two patterns of resistance¨: One group of patients is characterized by reduced numbers of tumor-infiltrating CD8+ T cells and reduced expression of PD-L1 after development of resistance, whereas the other group shows high CD8+ T cell infiltration and high expression of PD-L1 in addition to markedly elevated expression of other immune-inhibitory molecules. In two cases, we detect downregulation of type I and II IFN pathways following progression to resistance, which could lead to an impaired anti-tumor immune response. This study thus captures the development of immune checkpoint inhibitor resistance as it progresses and deepens our mechanistic understanding of immunotherapy response in NSCLC.

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Section: Discussionmentioning

confidence: 99%

Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype

Hiltbrunner,

Cords,

Kasser

et al. 2023

Nat Commun

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“…BRAFi resistance is a complex process shaped by the high heterogeneity and plasticity of TME under the intense drug‐driven crosstalk occurring between cancer and noncancer cells. The tumor phenotype plasticity is the core of the well‐known phenotype‐switch model, characterized by EMT guiding the shift from a proliferative phenotype, distinguished by MITF high status, to an invasive one enriched with the most prominent resistance marker AXL high but with coexisting MITF high cancer cells 37,38 . Importantly, the dominance of AXL signaling stimulates immune suppression in the TME 39 .…”

Section: Discussionmentioning

confidence: 99%

“…status, to an invasive one enriched with the most prominent resistance marker AXL high but with coexisting MITF high cancer cells. 37,38 Importantly, the dominance of AXL signaling stimulates immune suppression in the TME. 39 In this article, we provide evidence that romidepsin and IFN combination exerts antitumor and immunogenic effects against BRAF-mutated melanoma cells and breaks acquired VEM-resistance of these cells along with the inhibition of MITF/AXL expression.…”

Section: Noteworthy Upon Phagocytosis Of Drug-treated Melanoma Cellsmentioning

confidence: 99%

Reversing vemurafenib‐resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects

Fragale,

Stellacci,

Romagnoli

et al. 2023

Intl Journal of Cancer

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BRAF V600 mutations are the most common oncogenic alterations in melanoma cells, supporting proliferation, invasion, metastasis and immune evasion. In patients, these aberrantly activated cellular pathways are inhibited by BRAFi whose potent antitumor effect and therapeutic potential are dampened by the development of resistance.Here, by using primary melanoma cell lines, generated from lymph node lesions of metastatic patients, we show that the combination of two FDA-approved drugs, the histone deacetylate inhibitor (HDCAi) romidepsin and the immunomodulatory agent IFN-α2b, reduces melanoma proliferation, long-term survival and invasiveness and overcomes acquired resistance to the BRAFi vemurafenib (VEM). Targeted resequencing revealed that each VEM-resistant melanoma cell line and the parental counterpart are characterized by a distinctive and similar genetic fingerprint, shaping the differential and specific antitumor modulation of MAPK/AKT pathways by combined

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“…The MAP-kinase pathway has a pivotal role in cellular proliferation in tumors like melanomas 21 . In the invasive and resistant melanoma cell lines, 229R and 238R, over-activation of MAPK was observed as a result of phenotypic switching.…”

Section: Cell Intrinsic Pathways Involved In Breast Cancer Plasticitymentioning

confidence: 99%

The Unholy Trinity- Cancer cell plasticity, drug resistance and therapeutic opportunities

Chatterjee

Pulipaka

Subbalakshmi

et al. 2023

Preprint

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Cancer cell plasticity is the ability of tumor cells to switch phenotypes and is one of the predominant requisites of cancer cells capable of undergoing metastasis. Cancer cell plasticity is also recognised as one of the major contributors to intra-tumoral heterogeneity, a critical factor underlying the progression of malignant tumors which is known to modify tumor response and induce resistance against various modes of therapy thus posing a barrier to efficient cancer management. Cancer cell plasticity is acquired by the subversion of cell signaling pathways like MAPK, PI3K, STAT3, Wnt, Hedgehog and Notch as well as cellular programs such as epithelial to mesenchymal transition (EMT) and phenotypic plasticity. This complex phenomenon has been studied in many cancer types like pancreatic cancer, colon cancer and breast cancer. Some cancers like breast cancer are known to exhibit a hierarchical organization with cancer stem cells (CSCs) at the pinnacle of the pyramid due to their ability to promote tumorigenesis, metastasis and therapy resistance. CSCs which can undergo phenotypic changes resulting in heterogenous cell populations with differing potential to develop programs necessary for the metastatic process lies at the core of the cancer cell plasticity hypothesis. Our expanding knowledge of this field can lead to the development of more therapeutic strategies that can be used in cancer and other solid tumors that exhibit similar mechanisms of plasticity. This review will explore the current understanding we have of breast cancer on the intrinsic molecular mechanisms of cancer cell plasticity and the resistance to various types of cancer therapy that arise as a result of plasticity. We conclude by exploring the potential novel therapies that specifically target the pathways leading to plasticity and can be leveraged to treat patients living with the disease. Keywords: Cancer cell plasticity, Epithelial to Mesenchymal Transition (EMT), therapy resistance, targeted therapy.

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Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation

Cited by 9 publications

References 50 publications

Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype

Acquired resistance to anti-PD1 therapy in patients with NSCLC associates with immunosuppressive T cell phenotype

Reversing vemurafenib‐resistance in primary melanoma cells by combined romidepsin and type I IFN treatment through blocking of tumorigenic signals and induction of immunogenic effects

The Unholy Trinity- Cancer cell plasticity, drug resistance and therapeutic opportunities

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