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1.
Nat Commun ; 13(1): 7047, 2022 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396656

RESUMO

Chemotherapy can eradicate a majority of cancer cells. However, a small population of tumor cells often survives drug treatments through genetic and/or non-genetic mechanisms, leading to tumor recurrence. Here we report a reversible chemoresistance phenotype regulated by the mTOR pathway. Through a genome-wide CRISPR knockout library screen in pancreatic cancer cells treated with chemotherapeutic agents, we have identified the mTOR pathway as a prominent determinant of chemosensitivity. Pharmacological suppression of mTOR activity in cancer cells from diverse tissue origins leads to the persistence of a reversibly resistant population, which is otherwise eliminated by chemotherapeutic agents. Conversely, activation of the mTOR pathway increases chemosensitivity in vitro and in vivo and predicts better survival among various human cancers. Persister cells display a senescence phenotype. Inhibition of mTOR does not induce cellular senescence per se, but rather promotes the survival of senescent cells through regulation of autophagy and G2/M cell cycle arrest, as revealed by a small-molecule chemical library screen. Thus, mTOR plays a causal yet paradoxical role in regulating chemotherapeutic response; inhibition of the mTOR pathway, while suppressing tumor expansion, facilitates the development of a reversible drug-tolerant senescence state.


Assuntos
Neoplasias , Serina-Treonina Quinases TOR , Humanos , Proliferação de Células , Serina-Treonina Quinases TOR/metabolismo , Senescência Celular , Autofagia/fisiologia , Neoplasias/patologia
2.
BMC Cancer ; 21(1): 237, 2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33676427

RESUMO

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC), one of the most lethal cancers, is driven by oncogenic KRAS mutations. Farnesyl thiosalicylic acid (FTS), also known as salirasib, is a RAS inhibitor that selectively dislodges active RAS proteins from cell membrane, inhibiting downstream signaling. FTS has demonstrated limited therapeutic efficacy in PDAC patients despite being well tolerated. METHODS: To improve the efficacy of FTS in PDAC, we performed a genome-wide CRISPR synthetic lethality screen to identify genetic targets that synergize with FTS treatment. Among the top candidates, multiple genes in the endoplasmic reticulum-associated protein degradation (ERAD) pathway were identified. The role of ERAD inhibition in enhancing the therapeutic efficacy of FTS was further investigated in pancreatic cancer cells using pharmaceutical and genetic approaches. RESULTS: In murine and human PDAC cells, FTS induced unfolded protein response (UPR), which was further augmented upon treatment with a chemical inhibitor of ERAD, Eeyarestatin I (EerI). Combined treatment with FTS and EerI significantly upregulated the expression of UPR marker genes and induced apoptosis in pancreatic cancer cells. Furthermore, CRISPR-based genetic ablation of the key ERAD components, HRD1 and SEL1L, sensitized PDAC cells to FTS treatment. CONCLUSION: Our study reveals a critical role for ERAD in therapeutic response of FTS and points to the modulation of UPR as a novel approach to improve the efficacy of FTS in PDAC treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Degradação Associada com o Retículo Endoplasmático/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Sistemas CRISPR-Cas/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Degradação Associada com o Retículo Endoplasmático/genética , Farneseno Álcool/análogos & derivados , Farneseno Álcool/farmacologia , Farneseno Álcool/uso terapêutico , Técnicas de Inativação de Genes , Humanos , Hidrazonas/farmacologia , Hidrazonas/uso terapêutico , Hidroxiureia/análogos & derivados , Hidroxiureia/farmacologia , Hidroxiureia/uso terapêutico , Camundongos , Neoplasias Pancreáticas/patologia , Proteínas/genética , Salicilatos/farmacologia , Salicilatos/uso terapêutico , Mutações Sintéticas Letais , Ubiquitina-Proteína Ligases/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos
3.
J Proteome Res ; 20(1): 858-866, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33289385

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers. Dissecting the tumor cell proteome from that of the non-tumor cells in the PDAC tumor bulk is critical for tumorigenesis studies, biomarker discovery, and development of therapeutics. However, investigating the tumor cell proteome has proven evasive due to the tumor's extremely complex cellular composition. To circumvent this technical barrier, we have combined bioorthogonal noncanonical amino acid tagging (BONCAT) and data-independent acquisition mass spectrometry (DIA-MS) in an orthotopic PDAC model to specifically identify the tumor cell proteome in vivo. Utilizing the tumor cell-specific expression of a mutant tRNA synthetase transgene, this approach provides tumor cells with the exclusive ability to incorporate an azide-bearing methionine analogue into newly synthesized proteins. The azide-tagged tumor cell proteome is subsequently enriched and purified via a bioorthogonal reaction and then identified and quantified using DIA-MS. Applying this workflow to the orthotopic PDAC model, we have identified thousands of proteins expressed by the tumor cells. Furthermore, by comparing the tumor cell and tumor bulk proteomes, we showed that the approach can distinctly differentiate proteins produced by tumor cells from those of non-tumor cells within the tumor microenvironment. Our study, for the first time, reveals the tumor cell proteome of PDAC under physiological conditions, providing broad applications for tumorigenesis, therapeutics, and biomarker studies in various human cancers.


Assuntos
Aminoacil-tRNA Sintetases , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Aminoácidos , Azidas , Carcinoma Ductal Pancreático/genética , Humanos , Neoplasias Pancreáticas/genética , Proteoma/genética , Microambiente Tumoral
4.
J Hematol Oncol ; 13(1): 61, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32487143

RESUMO

Cellular homeostasis requires the proper nuclear-cytoplasmic partitioning of large molecules, which is often deregulated in cancer. XPO1 is an export receptor responsible for the nuclear-cytoplasmic transport of hundreds of proteins and multiple RNA species. XPO1 is frequently overexpressed and/or mutated in human cancers and functions as an oncogenic driver. Suppression of XPO1-mediated nuclear export, therefore, presents a unique therapeutic strategy. In this review, we summarize the physiological functions of XPO1 as well as the development of various XPO1 inhibitors and provide an update on the recent clinical trials of the SINE compounds. We also discuss potential future research directions on the molecular function of XPO1 and the clinical application of XPO1 inhibitors.


Assuntos
Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Antineoplásicos/farmacologia , Carioferinas/antagonistas & inibidores , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Previsões , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Hidrazinas/efeitos adversos , Hidrazinas/uso terapêutico , Carioferinas/fisiologia , Proteínas de Neoplasias/metabolismo , RNA Neoplásico/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Proteína Exportina 1
5.
Int J Hematol Oncol ; 8(3): IJH19, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31850145

RESUMO

"Double-hit lymphomas with MYC and BCL2 translocations can be effectively treated by combined targeting of the driver oncogenes".

6.
J Hematol Oncol ; 12(1): 119, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752970

RESUMO

Double-hit lymphoma (DHL) is among the most aggressive and chemoresistant lymphoma subtypes. DHLs carry genomic abnormalities in MYC, BCL2, and/or BCL6 oncogenes. Due to the simultaneous overexpression of these driver oncogenes, DHLs are highly resistant to frontline therapies. Most DHLs overexpress both MYC and BCL2 driver oncogenes concurrently. We reasoned that simultaneous suppression of the two driver oncogenes would be more effective in eradicating DHLs than inactivation of single oncogene. XPO1 is a receptor for nuclear cytoplasmic transport of protein and RNA species. Recently, XPO1 inhibition was shown to downregulate MYC expression in several cancer cell lines. We therefore examined the role of XPO1 as a therapeutic target in suppressing MYC function and the potential synergistic effects of simultaneous suppression of XPO1 and BCL2 in the treatment of DHL. Here, we demonstrate that XPO1 inhibition abrogates MYC protein expression and induces massive tumor cell apoptosis. Combined use of XPO1 and BCL2 inhibitors is highly effective in eradicating DHL cells in cell culture. Notably, in a mouse model of DHL bearing primary tumor cells derived from lymphoma patients, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression, prevents brain metastasis, and extends host survival. Thus, our study confirms the simultaneous targeting of MYC and BCL2 driver oncogenes through the combined use of XPO1 and BCL2 inhibitors as a unique approach for the treatment of DHLs.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Carioferinas/antagonistas & inibidores , Linfoma/tratamento farmacológico , Linfoma/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores , Rearranjo Gênico , Humanos , Carioferinas/genética , Linfoma/patologia , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptores Citoplasmáticos e Nucleares/genética , Translocação Genética , Proteína Exportina 1
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