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1.
NPJ Precis Oncol ; 8(1): 20, 2024 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-38273040

RESUMO

Utility of PI3Kα inhibitors like BYL719 is limited by the acquisition of genetic and non-genetic mechanisms of resistance which cause disease recurrence. Several combination therapies based on PI3K inhibition have been proposed, but a way to systematically prioritize them for breast cancer treatment is still missing. By integrating published and in-house studies, we have developed in silico models that quantitatively capture dynamics of PI3K signaling at the network-level under a BYL719-sensitive versus BYL719 resistant-cell state. Computational predictions show that signal rewiring to alternative components of the PI3K pathway promote resistance to BYL719 and identify PDK1 as the most effective co-target with PI3Kα rescuing sensitivity of resistant cells to BYL719. To explore whether PI3K pathway-independent mechanisms further contribute to BYL719 resistance, we performed phosphoproteomics and found that selection of high levels of the cell cycle regulator p21 unexpectedly promoted drug resistance in T47D cells. Functionally, high p21 levels favored repair of BYL719-induced DNA damage and bypass of the associated cellular senescence. Importantly, targeted inhibition of the check-point inhibitor CHK1 with MK-8776 effectively caused death of p21-high T47D cells, thus establishing a new vulnerability of BYL719-resistant breast cancer cells. Together, our integrated studies uncover hidden molecular mediators causing resistance to PI3Kα inhibition and provide a framework to prioritize combination therapies for PI3K-mutant breast cancer.

2.
STAR Protoc ; 2(3): 100765, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34485937

RESUMO

3D cultures of mammary epithelial cells purified from murine models provide a unique resource to study genetically defined breast cancer and response to targeted therapies. Here, we describe step-by-step experimental procedures for the successful establishment of murine mammary organoid lines isolated from mammary glands or mammary tumors driven by mutations in components of the PI3K pathway. These detailed protocols also include procedures to perform assays that can be adopted to screen response to drug treatments and to inform better therapies. For details on potential applications and use of this protocol, please refer to Yip et al. (2020).


Assuntos
Glândulas Mamárias Animais/citologia , Neoplasias Mamárias Experimentais/patologia , Técnicas de Cultura de Órgãos/métodos , Organoides , Fosfatidilinositol 3-Quinases/genética , Animais , Morte Celular/fisiologia , Criopreservação , Feminino , Glândulas Mamárias Animais/fisiologia , Neoplasias Mamárias Experimentais/genética , Redes e Vias Metabólicas , Camundongos Endogâmicos C57BL , Técnicas de Cultura de Órgãos/instrumentação , Fosfatidilinositol 3-Quinases/metabolismo
3.
Cells ; 10(3)2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33809714

RESUMO

Molecular alterations in cancer genes and associated signaling pathways are used to inform new treatments for precision medicine in cancer. Small molecule inhibitors and monoclonal antibodies directed at relevant cancer-related proteins have been instrumental in delivering successful treatments of some blood malignancies (e.g., imatinib with chronic myelogenous leukemia (CML)) and solid tumors (e.g., tamoxifen with ER positive breast cancer and trastuzumab for HER2-positive breast cancer). However, inherent limitations such as drug toxicity, as well as acquisition of de novo or acquired mechanisms of resistance, still cause treatment failure. Here we provide an up-to-date review of the successes and limitations of current targeted therapies for cancer treatment and highlight how recent technological advances have provided a new level of understanding of the molecular complexity underpinning resistance to cancer therapies. We also raise three basic questions concerning cancer drug discovery based on molecular markers and alterations of selected signaling pathways, and further discuss how combination therapies may become the preferable approach over monotherapy for cancer treatments. Finally, we consider novel therapeutic developments that may complement drug delivery and significantly improve clinical response and outcomes of cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Tomada de Decisão Clínica , Desenvolvimento de Medicamentos , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Medicina de Precisão
4.
Proc Natl Acad Sci U S A ; 117(45): 28056-28067, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33097662

RESUMO

The Rac-GEF, P-Rex1, activates Rac1 signaling downstream of G protein-coupled receptors and PI3K. Increased P-Rex1 expression promotes melanoma progression; however, its role in breast cancer is complex, with differing reports of the effect of its expression on disease outcome. To address this we analyzed human databases, undertook gene array expression analysis, and generated unique murine models of P-Rex1 gain or loss of function. Analysis of PREX1 mRNA expression in breast cancer cDNA arrays and a METABRIC cohort revealed that higher PREX1 mRNA in ER+ve/luminal tumors was associated with poor outcome in luminal B cancers. Prex1 deletion in MMTV-neu or MMTV-PyMT mice reduced Rac1 activation in vivo and improved survival. High level MMTV-driven transgenic PREX1 expression resulted in apicobasal polarity defects and increased mammary epithelial cell proliferation associated with hyperplasia and development of de novo mammary tumors. MMTV-PREX1 expression in MMTV-neu mice increased tumor initiation and enhanced metastasis in vivo, but had no effect on primary tumor growth. Pharmacological inhibition of Rac1 or MEK1/2 reduced P-Rex1-driven tumoroid formation and cell invasion. Therefore, P-Rex1 can act as an oncogene and cooperate with HER2/neu to enhance breast cancer initiation and metastasis, despite having no effect on primary tumor growth.


Assuntos
Fatores de Troca do Nucleotídeo Guanina , Neoplasias Mamárias Experimentais , Metástase Neoplásica , Animais , Polaridade Celular/genética , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Masculino , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Camundongos Transgênicos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica/genética , Metástase Neoplásica/patologia
5.
PLoS One ; 13(6): e0199412, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29928021

RESUMO

Although small intestinal epithelial stem cells form crypts when using intestinal culture conditions, colon stem cells usually form colonospheres. Colon mesenchymal cell feeder layers can stimulate colon crypts to form organoids and produce crypts. We have investigated whether conditioned medium from colon mesenchymal cells can also stimulate colonosphere and organoid cryptogenesis. We prepared conditioned medium (CM) from WEHI-YH2 cells (mouse colon myofibroblasts); the CM stimulated both colonosphere formation and organoid cryptogenesis in vitro. The colon organoid-stimulating factors in WEHI-YH2 CM are inactivated by heating and trypsin digestion and proteins can be concentrated by ultrafiltration. Both the colonosphere- and organoid cryptogenesis- stimulatory effects of the CM are independent of canonical Wnt and Notch signaling. In contrast, bone morphogenetic protein 4 (BMP4) abolishes colonosphere formation and organoid cryptogenesis. The Transforming Growth Factor beta (TGFß) Type I receptor kinase inhibitor (A83-01) stimulates colonosphere formation, whereas the Epidermal Growth Factor receptor (EGFR) kinase inhibitor (AG1478) reduces the formation of colonospheres, but in the presence of EGF, a "just-right" concentration of AG1478 increases colon organoid cryptogenesis.


Assuntos
Colo/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Microvilosidades/metabolismo , Miofibroblastos/metabolismo , Organoides/crescimento & desenvolvimento , Animais , Biomarcadores/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Colo/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Células Alimentadoras/citologia , Camundongos Endogâmicos C57BL , Microvilosidades/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Organoides/efeitos dos fármacos , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares/citologia , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Células-Tronco/efeitos dos fármacos , Células-Tronco/metabolismo , Proteínas Wnt/metabolismo
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