RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer

Sanz-Moreno, Adrián; Palomeras, Sònia; Pedersen, Kim; Morancho, Beatriz; Pascual, Tomás; Galván, Patricia; Benítez, Sandra; Gómez-Miragaya, Jorge; Ciscar, Marina; Jiménez, María; Pernas, Sònia; Petit, Audrey; Soler-Monsó, María Teresa; Viñas, Gemma; Alsaleem, Mansour; Rakha, Emad A.; Green, Andrew; Santamarı́a, Patricia G.; Mulder, Celine; Lemeer, Simone; Arribas, Joaquı́n; Prat, Aleix; Puig, Teresa; Gonzalez-Suarez, Eva

doi:10.1186/s13058-021-01390-2

Cited by 15 publications

(8 citation statements)

References 59 publications

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“…HER2 activates NF-κB via IKKα, promoting tumor progression in ERnegative/HER2+ BCa cells in response to RANK signaling [7,123]. It was recently demonstrated that RANK and RANKL were more frequent in HER2+ tumors with acquired resistance to anti-HER2 therapies, and that RANK expression increased after dual anti-HER2 neoadjuvant therapy in the SOLTI-1114 PAMELA trial cohort [124]. In this study, it was shown that RANKL stimulation increased NF-κB activation in lapatinib-resistant HER2+ cell lines compared to their sensitive counterparts, whereas RANK loss sensitized lapatinib-resistant cells to the drug in vitro.…”

Section: Aggressivenessmentioning

confidence: 99%

The Roadmap of RANKL/RANK Pathway in Cancer

Casimiro

Vilhais

Gomes

et al. 2021

Cells

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The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

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Section: Aggressivenessmentioning

confidence: 99%

The Roadmap of RANKL/RANK Pathway in Cancer

Casimiro

Vilhais

Gomes

et al. 2021

Cells

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“…For the MAPK pathway, we evaluated ERK 1/2 (ERK) and P38 activation based on previous studies reporting the role of these signaling nodes in HER2-positive breast cancer and drug resistance [ 68 , 69 , 70 ]. Interestingly, we identified common variations in pERK levels in all the resistant cell lines (except AU-565.rTP), suggesting their association with resistance mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines

Sanz-Álvarez,

Luque,

Morales-Gallego

et al. 2023

IJMS

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The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to trastuzumab alone. However, despite initial therapeutic success, most patients eventually progress, and tumors develop acquired resistance and invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance in order to develop targeted therapeutic strategies with improved efficacy. We generated four novel HER2-positive cell lines via prolonged exposure to trastuzumab and pertuzumab and determined their resistance rates. Long-term resistance was confirmed by a significant increase in the colony-forming capacity of the derived cells. We authenticated the molecular identity of the new lines via both immunohistochemistry for the clinical phenotype and molecular profiling of point mutations. HER2 overexpression was confirmed in all resistant cell lines, and acquisition of resistance to trastuzumab and pertuzumab did not translate into differences in ER, PR, and HER2 receptor expression. In contrast, changes in the expression and activity of other HER family members, particularly HER4, were observed. In the same vein, analyses of the receptor and effector kinase status of different cellular pathways revealed that the MAPK pathway may be involved in the acquisition of resistance to trastuzumab and pertuzumab. Finally, proteomic analysis confirmed a significant change in the abundance patterns of more than 600 proteins with implications in key biological processes, such as ribosome formation, mitochondrial activity, and metabolism, which could be relevant mechanisms in the generation of resistance in HER2-positive breast cancer. We concluded that these resistant BCCLs may be a valuable tool to better understand the mechanisms of acquisition of resistance to trastuzumab and pertuzumab-based anti-HER2 therapy.

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“…Sanz-Moreno et al (2021) described activating the RANKL signaling pathway raises extracellular signal-regulated kinase (ERK), NF-κB signaling, and lapatinib resistance in several human epidermal growth factor receptor 2 (HER2)-positive BC cells. On the other hand, the receptor activator of NF-κB-B (RANK) signaling deactivation sensitizes lapatinib-resistant BC cells to the drug [ 102 ]. Another study revealed that NF-κB activation is a crucial adaptive survival mechanism of cancer cells induced by the epidermal growth factor receptor (EGFR) oncogene (it is also known as an ErbB).…”

Section: The Nf-κb Signaling-induced Cell Plasticity and The Developm...mentioning

confidence: 99%

Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling

Kubatka,

Koklesova,

Mazurakova

et al. 2023

Cancer Metastasis Rev

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Cancer cell plasticity plays a crucial role in tumor initiation, progression, and metastasis and is implicated in the multiple cancer defense mechanisms associated with therapy resistance and therapy evasion. Cancer resistance represents one of the significant obstacles in the clinical management of cancer. Some reversal chemosensitizing agents have been developed to resolve this serious clinical problem, but they have not yet been proven applicable in oncological practice. Activated nuclear factor kappa B (NF-κB) is a frequently observed biomarker in chemoresistant breast cancer (BC). Therefore, it denotes an attractive cellular target to mitigate cancer resistance. We summarize that flavonoids represent an essential class of phytochemicals that act as significant regulators of NF-κB signaling and negatively affect the fundamental cellular processes contributing to acquired cell plasticity and drug resistance. In this regard, flavokawain A, icariin, alpinetin, genistein, wogonin, apigenin, oroxylin A, xanthohumol, EGCG, hesperidin, naringenin, orientin, luteolin, delphinidin, fisetin, norwogonin, curcumin, cardamonin, methyl gallate and catechin-3-O-gallate, ampelopsin, puerarin, hyperoside, baicalein, paratocarpin E, and kaempferol and also synthetic flavonoids such as LFG-500 and 5,3′-dihydroxy-3,6,7,8,4′-pentamethoxyflavone have been reported to specifically interfere with the NF-κB pathway with complex signaling consequences in BC cells and could be potentially crucial in re-sensitizing unresponsive BC cases. The targeting NF-κB by above-mentioned flavonoids includes the modification of tumor microenvironment and epithelial-mesenchymal transition, growth factor receptor regulations, and modulations of specific pathways such as PI3K/AKT, MAP kinase/ERK, and Janus kinase/signal transduction in BC cells. Besides that, NF-κB signaling in BC cells modulated by flavonoids has also involved the regulation of ATP-binding cassette transporters, apoptosis, autophagy, cell cycle, and changes in the activity of cancer stem cells, oncogenes, or controlling of gene repair. The evaluation of conventional therapies in combination with plasticity-regulating/sensitizing agents offers new opportunities to make significant progress towards a complete cure for cancer. Graphical abstract

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RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer

Cited by 15 publications

References 59 publications

The Roadmap of RANKL/RANK Pathway in Cancer

The Roadmap of RANKL/RANK Pathway in Cancer

Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines

Cell plasticity modulation by flavonoids in resistant breast carcinoma targeting the nuclear factor kappa B signaling

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