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Your search keyword '"631/67/1059/2326"' showing total 2 results
Start Over Descriptor "631/67/1059/2326" Publisher apollo - university of cambridge repository
2 results on '"631/67/1059/2326"'

1. SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca 2+ flux to mitochondria

Author

Xue, Yibo, Morris, Jordan L., Yang, Kangning, Fu, Zheng, Zhu, Xianbing, Johnson, Fraser, Meehan, Brian, Witkowski, Leora, Yasmeen, Amber, Golenar, Tunde, Coatham, Mackenzie, Morin, Geneviève, Monast, Anie, Pilon, Virginie, Fiset, Pierre Olivier, Jung, Sungmi, Gonzalez, Anne V., Camilleri-Broet, Sophie, Fu, Lili, Postovit, Lynne-Marie, Spicer, Jonathan, Gotlieb, Walter H., Guiot, Marie-Christine, Rak, Janusz, Park, Morag, Lockwood, William, Foulkes, William D., Prudent, Julien, and Huang, Sidong

Subjects
631/80/82/23, 631/67/1059/2326, 49/47, article, 13/106, 3. Good health, 631/67/68/2486, 13/31, 13/2, 82/80, 13/44, 631/67/1244, 13/95, 13/51, 38/39, 14/19, 38/15, 13/89
Abstract

Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.

2. The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Author

Trigg, Ricky M., Lee, Liam C., Prokoph, Nina, Jahangiri, Leila, Reynolds, C. Patrick, Amos Burke, G. A., Probst, Nicola A., Han, Miaojun, Matthews, Jamie D., Lim, Hong Kai, Manners, Eleanor, Martinez, Sonia, Pastor, Joaquin, Blanco-Aparicio, Carmen, Merkel, Olaf, De Los Fayos Alonso, Ines Garces, Kodajova, Petra, Tangermann, Simone, Högler, Sandra, Luo, Ji, Kenner, Lukas, and Turner, Suzanne D.

Subjects
82/29, 631/67/1059/2326, 45/41, 49/22, 49/23, 38/90, 45/22, 13/106, 45/23, 13/109, 45/47, 96/31, Article, 96/95, 13/2, 13/1, 38/1, 42/47, 42/89, hemic and lymphatic diseases, 38/23, 38/89, 38/22, 96/2, 96/1, 13/89, 38/109, 96/106, 45/77, 64/110, 3. Good health, 13/31, 631/67/1059/602, 631/67/2332, 13/51, 13/95, 38/77, 64/60, 631/67/70, 82/1, 82/51
Abstract

Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

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