RESUMO
Intrinsic and acquired resistance to anti-EGFR antibody therapy, frequently mediated by a mutant or amplified KRAS oncogene, is a significant challenge in the treatment of colorectal cancer (CRC). However, the mechanism of KRAS-mediated therapeutic resistance is not well understood. In this study, we demonstrate that clinically used anti-EGFR antibodies, including cetuximab and panitumumab, induce killing of sensitive CRC cells through p73-dependent transcriptional activation of the pro-apoptotic Bcl-2 family protein PUMA. PUMA induction and p73 activation are abrogated in CRC cells with acquired resistance to anti-EGFR antibodies due to KRAS alterations. Inhibition of aurora kinases preferentially kills mutant KRAS CRC cells and overcomes KRAS-mediated resistance to anti-EGFR antibodies in vitro and in vivo by restoring PUMA induction. Our results suggest that PUMA plays a critical role in meditating the sensitivity of CRC cells to anti-EGFR antibodies, and that restoration of PUMA-mediated apoptosis is a promising approach to improve the efficacy of EGFR-targeted therapy.
Assuntos
Anticorpos Monoclonais/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Cetuximab/farmacologia , Receptores ErbB/metabolismo , Feminino , Células HCT116 , Humanos , Camundongos , Camundongos Nus , Panitumumabe/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismoRESUMO
A sugar poly(orthoester)-based drug delivery system was constructed to achieve acidity-enhanced drug delivery and cell killing.
Assuntos
Carboidratos/química , Portadores de Fármacos/química , Interações Hidrofóbicas e Hidrofílicas , Nanoestruturas/química , Poliésteres/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Células HEK293 , Humanos , Concentração de Íons de HidrogênioRESUMO
Mutations in the KRAS oncogene represent one of the most prevalent genetic alterations in colorectal cancer (CRC), the third leading cause of cancer-related death in the US. In addition to their well-characterized function in driving tumor progression, KRAS mutations have been recognized as a critical determinant of the therapeutic response of CRC. Recent studies demonstrate that KRAS-mutant tumors are intrinsically insensitive to clinically-used epidermal growth factor receptor (EGFR) targeting antibodies, including cetuximab and panitumumab. Acquired resistance to the anti-EGFR therapy was found to be associated with enrichment of KRAS-mutant tumor cells. However, the underlying molecular mechanism of mutant-KRAS-mediated therapeutic resistance has remained unclear. Despite intensive efforts, directly targeting mutant KRAS has been largely unsuccessful. This review summarizes the recent advances in understanding the biological function of KRAS mutations in determining the therapeutic response of CRC, highlighting several recently developed agents and strategies for targeting mutant KRAS, such as synthetic lethal interactions.
RESUMO
The synthesis of clickable polysaccharides was achieved by using alkynylated 1,6-anhydro glucopyranose as a monomer and BF3·OEt2 as an effective catalyst. Subsequent click conjugation with polyethylene glycol (PEG) afforded PEG-grafted polysaccharides in nearly quantitative efficiency.
Assuntos
Nanopartículas/química , Polissacarídeos/química , Boranos/química , Catálise , Sobrevivência Celular/efeitos dos fármacos , Química Click , Células HCT116 , Humanos , Nanopartículas/toxicidade , Polietilenoglicóis/química , Polissacarídeos/síntese químicaRESUMO
Aurora kinases play a key role in mitosis and are frequently overexpressed in a variety of tumor cells. Inhibition of aurora kinases results in mitotic arrest and death of cancer cells, and has been explored as an anticancer strategy. However, how aurora inhibition kills cancer cells is poorly understood. In this study, we found that inhibition of aurora kinases by siRNA or small-molecule inhibitors led to induction of p53 upregulated modulator of apoptosis (PUMA), a BH3-only Bcl-2 family protein, in colorectal cancer cells irrespective of p53 status. Deficiency in PUMA increased polyploidy, improved cell survival, and abrogated mitochondria-mediated apoptosis induced by aurora kinase inhibitors. In response to aurora kinase inhibition, PUMA was directly activated by p65 through the canonical NF-κB pathway following AKT inhibition. Furthermore, PUMA was necessary for the chemosensitization and in vivo antitumor effects of aurora kinase inhibitors in colon cancer cells. These results suggest that PUMA induction mediates the apoptotic response to mitotic arrest imposed by aurora kinase inhibition, and may be a useful indicator for the anticancer activity of aurora kinase inhibitors.