Differential responses to kinase inhibition in FGFR2-addicted triple negative breast cancer cells: a quantitative phosphoproteomics study

Cunningham, Debbie L.; Sarhan, Adil R.; Creese, Andrew J.; Larkins, Katherine P. B.; Zhao, Hongyan; Ferguson, Harriet R.; Brookes, Katie; Marusiak, Anna A.; Cooper, Helen J.; Heath, John K.

doi:10.1038/s41598-020-64534-y

Cited by 13 publications

(9 citation statements)

References 132 publications

(163 reference statements)

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“…Strikingly, the AAMDC KD induced enlarged LAMP2 + late endosomal vesicles, which exhibited a degree of positive staining for p-mTOR S2448 (Supplementary Fig. 3b ) and fibroblast growth factor receptor 2 (FGFR2), which is overexpressed in IntClust2 SUM52PE cells and confers activation of PI3K 20 (Supplementary Fig. 7b ).…”

Section: Resultsmentioning

confidence: 99%

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

et al. 2021

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Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.

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Section: Resultsmentioning

confidence: 99%

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

et al. 2021

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“…The MAPK pathway, including ERK1/2, JNK and p38 kinases [ 16 – 18 ], regulates transcription [ 19 ] and recruits negative signalling regulators like the E3 ligase CBL, the adaptor SPROUTY and the phosphatase SHP2 [ 20 , 21 ]. By contrast, AKT induces the activation of the mTOR complex 1 [ 22 ] and the phosphorylation of the FOXO1 transcription factor [ 23 ] ( figure 2 c ). Following recruitment to activated FGFR the enzyme PLCγ induces calcium ion release, resulting in the activation of downstream kinases like PKC [ 24 ] ( figure 2 c ).…”

Section: Overview Of Fgfr Signallingmentioning

confidence: 99%

“…The FGFR2 gene is located on the 10q26.13 chromosomal region, which is amplified in only 5% of all breast cancer patients, in particular TNBC patients [ 199 ]. In TNBC, FGFR2 amplification has been associated with robust activation of signalling, cellular transformation and resistance to FGFR inhibitors in pre-clinical models [ 3 , 22 , 103 , 200 ]. However, very recently it has been reported that FGFR2 can be expressed also in ER/PR-positive tumours where, surprisingly, low FGFR2 expression correlates with poor prognosis [ 201 ] ( figure 4 ).…”

Section: Fgfrs In Breast Cancermentioning

confidence: 99%

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

Francavilla

O'Brien

2022

Open Biol.

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Fibroblast Growth Factor Receptor (FGFR) signalling plays a critical role in breast embryonal development, tissue homeostasis, tumorigenesis and metastasis. FGFR, its numerous FGF ligands and signalling partners are often dysregulated in breast cancer progression and are one of the causes of resistance to treatment in breast cancer. Furthermore, FGFR signalling on epithelial cells is affected by signals from the breast microenvironment, therefore increasing the possibility of breast developmental abnormalities or cancer progression. Increasing our understanding of the multi-layered roles of the complex family of FGFRs, their ligands FGFs and their regulatory partners may offer novel treatment strategies for breast cancer patients, as a single agent or rational co-target, which will be explored in depth in this review.

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“…It has become increasingly appreciated that the mechanisms underpinning adaptive resistance can be highly heterogeneous and context-specific, even in response to the same drug compounds (45). This is primarily driven by variation in protein expression and/or mutational profiles observed across and within different cancer cell types, resulting in context-specific differences in feedback and crosstalk strengths that impact on drug response (19,28).…”

Section: Discussionmentioning

confidence: 99%

Integrative Modelling of Signalling Network Dynamics Identifies Cell Type-selective Therapeutic Strategies for FGFR4-driven Cancers

Shin

Chew

Ghomlaghi

et al. 2021

Preprint

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Oncogenic FGFR4 signalling represents a potential therapeutic target in many cancer types, including triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC). However, resistance to single-agent therapy directed at FGFR4 remains a major challenge, prompting the need to identify more effective combinatorial therapeutic strategies. Here, we integrated computational network modelling and experimental validation to characterise dynamic reprogramming of the FGFR4 signalling network in TNBC following FGFR4 kinase inhibition. We found that AKT, which signals downstream of FGFR4, displayed a rapid and potent reactivation following FGFR4 targeting. Through model-based simulation and systematic prediction of the effect of co-targeting specific network nodes, we predicted, and validated experimentally, strong synergism of co-targeting FGFR4 and particular ErbB kinases or AKT, but not the upstream kinase PI3K. Further, incorporation of protein expression data from hundreds of cancer cell types enabled us to adapt our model to other diverse cellular contexts, leading to the prediction that while AKT rebound occurs frequently, it is not a general phenomenon. Instead, ERK is reactivated in a subset of cell types, including the FGFR4-driven HCC cell line Hep3B. This was subsequently corroborated, and moreover, co-targeting FGFR4 and MEK in Hep3B cells markedly enhanced inhibition of cell proliferation. Overall, these findings provide novel insights into the dynamics of drug-induced network remodelling in cancer cells, highlight the impact of protein expression heterogeneity on network response to targeted therapy and identify candidate cell type-selective combination treatments for FGFR4-driven cancer.

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Differential responses to kinase inhibition in FGFR2-addicted triple negative breast cancer cells: a quantitative phosphoproteomics study

Abstract: Although these two triple-negative FGFR2-overexpressing cell lines both display an addiction to FGFR2 activation, it is apparent that the proteomic landscapes differ, which may impact on their global response to inhibitor treatment.

Cited by 13 publications

References 132 publications

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer

Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer

Integrative Modelling of Signalling Network Dynamics Identifies Cell Type-selective Therapeutic Strategies for FGFR4-driven Cancers

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