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Nat Commun ; 12(1): 4919, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389725


BRCA1 or BRCA2 germline mutations predispose to breast, ovarian and other cancers. High-throughput sequencing of tumour genomes revealed that oncogene amplification and BRCA1/2 mutations are mutually exclusive in cancer, however the molecular mechanism underlying this incompatibility remains unknown. Here, we report that activation of ß-catenin, an oncogene of the WNT signalling pathway, inhibits proliferation of BRCA1/2-deficient cells. RNA-seq analyses revealed ß-catenin-induced discrete transcriptome alterations in BRCA2-deficient cells, including suppression of CDKN1A gene encoding the CDK inhibitor p21. This accelerates G1/S transition, triggering illegitimate origin firing and DNA damage. In addition, ß-catenin activation accelerates replication fork progression in BRCA2-deficient cells, which is critically dependent on p21 downregulation. Importantly, we find that upregulated p21 expression is essential for the survival of BRCA2-deficient cells and tumours. Thus, our work demonstrates that ß-catenin toxicity in cancer cells with compromised BRCA1/2 function is driven by transcriptional alterations that cause aberrant replication and inflict DNA damage.

Proteína BRCA1/genética , Proteína BRCA2/genética , Oncogenes/genética , Transcrição Genética/genética , beta Catenina/genética , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Sobrevivência Celular/genética , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Dano ao DNA , Feminino , Perfilação da Expressão Gênica/métodos , Células HeLa , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , RNA-Seq/métodos , beta Catenina/metabolismo
Onco Targets Ther ; 13: 12301-12316, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33299326


In 2018, there were 400,000 new cases of renal cell carcinoma (RCC) globally, with 175,000 deaths attributable to the disease. Three quarters of patients have potentially curable localised disease at diagnosis; however, recurrence rates are as high as 40% following surgery. There are currently no adjuvant therapies in routine clinical use which reliably improve outcomes. Effective adjuvant therapy is an urgent unmet need to reduce recurrence risk and improve outcomes. Early efforts explored chemotherapy, radiotherapy, cytokine therapy, hormonal treatments and tumour cell vaccines as adjuvant therapies, however, have yielded disappointing results. More recently, interest shifted to evaluating tyrosine kinase inhibitors (TKIs) in the adjuvant setting, as they improve outcomes in metastatic disease. Five phase III clinical trials testing adjuvant use of a range of TKIs have been performed, with the results of a sixth trial awaited. Unfortunately, these studies have thus far yielded conflicting and disappointing results, and there is currently no strong evidence for routine adjuvant TKI therapy. In parallel, novel immunotherapy treatment approaches have recently been developed, transforming the management of a range of malignancies, particularly through immune checkpoint inhibitors (ICIs). These approaches are well established in the metastatic context in RCC, as well as in the adjuvant treatment of melanoma. On this basis, five phase III trials are currently ongoing to test the efficacy of a range of ICIs in adjuvant RCC patients, with initial results expected over the next few years. In this article, we review the current evidence for adjuvant therapies in RCC, discuss ongoing clinical trials and suggest directions for future work to address this unmet need.

Eur J Cancer ; 113: 87-95, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30991262


BACKGROUND: Pre-clinically, phosphoinositide 3-kinase (PI3K) inhibition radiosensitises tumours by increasing intrinsic radiosensitivity and by reducing tumour hypoxia. We assessed whether buparlisib, a class 1 PI3K inhibitor, can be safely combined with radiotherapy in patients with non-small cell lung carcinoma (NSCLC) and investigated its effect on tumour hypoxia. METHODS: This was a 3 + 3 dose escalation and dose expansion phase I trial in patients with advanced NSCLC. Buparlisib dose levels were 50 mg, 80 mg and 100 mg once daily orally for 2 weeks, with palliative thoracic radiotherapy (20 Gy in 5 fractions) delivered during week 2. Tumour hypoxic volume (HV) was measured using 18F-fluoromisonidazole positron-emission tomography-computed tomography at baseline and following 1 week of buparlisib. RESULTS: Twenty-one patients were recruited with 9 patients evaluable for maximum tolerated dose (MTD) analysis. No dose-limiting toxicity was reported; therefore, 100 mg was declared the MTD, and 10 patients received this dose in the expansion phase. Ninety-four percent of treatment-related adverse events were ≤grade 2 with fatigue (67%), nausea (24%) and decreased appetite (19%) most common per patient. One serious adverse event (grade 3 hypoalbuminaemia) was possibly related to buparlisib. No unexpected radiotherapy toxicity was reported. Ten (67%) of 15 patients evaluable for imaging analysis were responders with 20% median reduction in HV at the MTD. CONCLUSION: This is the first clinical trial to combine a PI3K inhibitor with radiotherapy in NSCLC and investigate the effects of PI3K inhibition on tumour hypoxia. This combination was well tolerated and PI3K inhibition reduced hypoxia, warranting investigation into whether this novel class of radiosensitisers can improve radiotherapy outcomes.

Adenocarcinoma de Pulmão/terapia , Aminopiridinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Pulmonares/terapia , Morfolinas/uso terapêutico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Radiossensibilizantes/uso terapêutico , Hipóxia Tumoral , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/metabolismo , Idoso , Anorexia/induzido quimicamente , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/metabolismo , Quimiorradioterapia , Fadiga/induzido quimicamente , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Misonidazol/análogos & derivados , Náusea/induzido quimicamente , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Radioterapia
Mol Cell ; 61(3): 449-460, 2016 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-26748828


G-quadruplex (G4)-forming genomic sequences, including telomeres, represent natural replication fork barriers. Stalled replication forks can be stabilized and restarted by homologous recombination (HR), which also repairs DNA double-strand breaks (DSBs) arising at collapsed forks. We have previously shown that HR facilitates telomere replication. Here, we demonstrate that the replication efficiency of guanine-rich (G-rich) telomeric repeats is decreased significantly in cells lacking HR. Treatment with the G4-stabilizing compound pyridostatin (PDS) increases telomere fragility in BRCA2-deficient cells, suggesting that G4 formation drives telomere instability. Remarkably, PDS reduces proliferation of HR-defective cells by inducing DSB accumulation, checkpoint activation, and deregulated G2/M progression and by enhancing the replication defect intrinsic to HR deficiency. PDS toxicity extends to HR-defective cells that have acquired olaparib resistance through loss of 53BP1 or REV7. Altogether, these results highlight the therapeutic potential of G4-stabilizing drugs to selectively eliminate HR-compromised cells and tumors, including those resistant to PARP inhibition.

Aminoquinolinas/farmacologia , Antineoplásicos/farmacologia , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Biomarcadores Tumorais/deficiência , Quadruplex G/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Ácidos Picolínicos/farmacologia , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mad2/genética , Proteínas Mad2/metabolismo , Masculino , Camundongos Nus , Terapia de Alvo Molecular , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Interferência de RNA , Telômero/efeitos dos fármacos , Telômero/genética , Telômero/metabolismo , Fatores de Tempo , Transfecção , Carga Tumoral/efeitos dos fármacos , Proteína 1 de Ligação à Proteína Supressora de Tumor p53 , Ensaios Antitumorais Modelo de Xenoenxerto
Chromosoma ; 124(2): 119-30, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25430998


Telomeres protect the ends of linear chromosomes against loss of genetic information and inappropriate processing as damaged DNA and are therefore crucial to the maintenance of chromosome integrity. In addition to providing a pathway for genome-wide DNA repair, homologous recombination (HR) plays a key role in telomere replication and capping. Consistent with this, the genomic instability characteristic of HR-deficient cells and tumours is driven in part by telomere dysfunction. Here, we discuss the mechanisms by which HR modulates the response to intrinsic cellular challenges that arise during telomere replication, as well as its impact on the assembly of telomere protective structures. How normal and tumour cells differ in their ability to maintain telomeres is deeply relevant to the search for treatments that would selectively eliminate cells whose capacity for HR-mediated repair has been compromised.

Recombinação Homóloga/genética , Telômero/genética , Animais , DNA/genética , Dano ao DNA , Reparo do DNA , Replicação do DNA , Instabilidade Genômica , Humanos , Mamíferos/genética , Neoplasias/genética , Telômero/metabolismo , Proteínas de Ligação a Telômeros/genética , Proteínas de Ligação a Telômeros/metabolismo
Nat Chem Biol ; 10(10): 853-60, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25195011


Activation of the ERK pathway is a hallmark of cancer, and targeting of upstream signaling partners led to the development of approved drugs. Recently, SCH772984 has been shown to be a selective and potent ERK1/2 inhibitor. Here we report the structural mechanism for its remarkable selectivity. In ERK1/2, SCH772984 induces a so-far-unknown binding pocket that accommodates the piperazine-phenyl-pyrimidine decoration. This new binding pocket was created by an inactive conformation of the phosphate-binding loop and an outward tilt of helix αC. In contrast, structure determination of SCH772984 with the off-target haspin and JNK1 revealed two canonical but distinct type I binding modes. Notably, the new binding mode with ERK1/2 was associated with slow binding kinetics in vitro as well as in cell-based assay systems. The described binding mode of SCH772984 with ERK1/2 enables the design of a new type of specific kinase inhibitors with prolonged on-target activity.

Antineoplásicos/química , Inibidores Enzimáticos/química , Indazóis/química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Piperazinas/química , Antineoplásicos/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Indazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cinética , Proteína Quinase 1 Ativada por Mitógeno/química , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/química , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/química , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Piperazinas/farmacologia , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo