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136


ULK1 inhibition overcomes compromised antigen presentation and restores antitumor immunity in LKB1 mutant lung cancer

Deng, Jiehui; Thennavan, Aatish; Dolgalev, Igor; Chen, Ting; Li, Jie; Marzio, Antonio; Poirier, John T; Peng, David; Bulatovic, Mirna; Mukhopadhyay, Subhadip; Silver, Heather; Papadopoulos, Eleni; Pyon, Val; Thakurdin, Cassandra; Han, Han; Li, Fei; Li, Shuai; Ding, Hailin; Hu, Hai; Pan, Yuanwang; Weerasekara, Vajira; Jiang, Baishan; Wang, Eric S; Ahearn, Ian; Philips, Mark; Papagiannakopoulos, Thales; Tsirigos, Aristotelis; Rothenberg, Eli; Gainor, Justin; Freeman, Gordon J; Rudin, Charles M; Gray, Nathanael S; Hammerman, Peter S; Pagano, Michele; Heymach, John V; Perou, Charles M; Bardeesy, Nabeel; Wong, Kwok-Kin
PMCID:8205437
PMID: 34142094
ISSN: 2662-1347
CID: 4917722

Breaking Tradition to Bridge Bench and Bedside: Accelerating the MD-PhD-Residency Pathway

Modrek, Aram S; Tanese, Naoko; Placantonakis, Dimitris G; Sulman, Erik P; Rivera, Rafael; Du, Kevin L; Gerber, Naamit K; David, Gregory; Chesler, Mitchell; Philips, Mark R; Cangiarella, Joan
PROBLEM/OBJECTIVE:Physician-scientists are individuals trained in both clinical practice and scientific research. Often, the goal of physician-scientist training is to address pressing questions in biomedical research. The established pathways to formally train such individuals are, mainly, MD-PhD programs and physician-scientist track residencies. Although graduates of these pathways are well equipped to be physician-scientists, numerous factors, including funding and length of training, discourage application to such programs and impede success rates. APPROACH/METHODS:To address some of the pressing challenges in training and retaining burgeoning physician-scientists, New York University Grossman School of Medicine formed the Accelerated MD-PhD-Residency Pathway in 2016. This pathway builds on the previously established accelerated three-year MD pathway to residency at the same institution. The Accelerated MD-PhD-Residency Pathway conditionally accepts MD-PhD trainees to a residency position at the same institution through the National Resident Matching Program. OUTCOMES/RESULTS:Since its inception, 2 students have joined the Accelerated MD-PhD-Residency Pathway, which provides protected research time in their chosen residency. The pathway reduces the time to earn an MD and PhD by one year and reduces the MD training phase to three years, reducing the cost and lowering socioeconomic barriers. Remaining at the same institution for residency allows for the growth of strong research collaborations and mentoring opportunities, which foster success. NEXT STEPS/UNASSIGNED:The authors and institutional leaders plan to increase the number of trainees that are accepted into the Accelerated MD-PhD-Residency Pathway and track the success of these students through residency and into practice to determine if the pathway is meeting its goal of increasing the number of practicing physician-scientists. The authors hope this model can serve as an example to leaders at other institutions who may wish to adopt this pathway for the training of their MD-PhD students.
PMID: 33464738
ISSN: 1938-808x
CID: 4760452

A small-molecule ICMT inhibitor delays senescence of Hutchinson-Gilford progeria syndrome cells

Chen, Xue; Yao, Haidong; Kashif, Muhammad; Revêchon, Gwladys; Eriksson, Maria; Hu, Jianjiang; Wang, Ting; Liu, Yiran; Tüksammel, Elin; Strömblad, Staffan; Ahearn, Ian M; Philips, Mark R; Wiel, Clotilde; Ibrahim, Mohamed X; Bergo, Martin O
A farnesylated and methylated form of prelamin A called progerin causes Hutchinson-Gilford progeria syndrome (HGPS). Inhibiting progerin methylation by inactivating the isoprenylcysteine carboxylmethyltransferase (ICMT) gene stimulates proliferation of HGPS cells and improves survival of Zmpste24-deficient mice. However, we don't know whether Icmt inactivation improves phenotypes in an authentic HGPS mouse model. Moreover, it is unknown whether pharmacologic targeting of ICMT would be tolerated by cells and produce similar cellular effects as genetic inactivation. Here, we show that knockout of Icmt improves survival of HGPS mice and restores vascular smooth muscle cell numbers in the aorta. We also synthesized a potent ICMT inhibitor called C75 and found that it delays senescence and stimulates proliferation of late-passage HGPS cells and Zmpste24-deficient mouse fibroblasts. Importantly, C75 did not influence proliferation of wild-type human cells or Zmpste24-deficient mouse cells lacking Icmt, indicating drug specificity. These results raise hopes that ICMT inhibitors could be useful for treating children with HGPS.
PMCID:7853716
PMID: 33526168
ISSN: 2050-084x
CID: 4798952

Scaffold association factor B (SAFB) is required for expression of prenyltransferases and RAS membrane association

Zhou, Mo; Kuruvilla, Leena; Shi, Xiarong; Viviano, Stephen; Ahearn, Ian M; Amendola, Caroline R; Su, Wenjuan; Badri, Sana; Mahaffey, James; Fehrenbacher, Nicole; Skok, Jane; Schlessinger, Joseph; Turk, Benjamin E; Calderwood, David A; Philips, Mark R
Inhibiting membrane association of RAS has long been considered a rational approach to anticancer therapy, which led to the development of farnesyltransferase inhibitors (FTIs). However, FTIs proved ineffective against KRAS-driven tumors. To reveal alternative therapeutic strategies, we carried out a genome-wide CRISPR-Cas9 screen designed to identify genes required for KRAS4B membrane association. We identified five enzymes in the prenylation pathway and SAFB, a nuclear protein with both DNA and RNA binding domains. Silencing SAFB led to marked mislocalization of all RAS isoforms as well as RAP1A but not RAB7A, a pattern that phenocopied silencing FNTA, the prenyltransferase α subunit shared by farnesyltransferase and geranylgeranyltransferase type I. We found that SAFB promoted RAS membrane association by controlling FNTA expression. SAFB knockdown decreased GTP loading of RAS, abrogated alternative prenylation, and sensitized RAS-mutant cells to growth inhibition by FTI. Our work establishes the prenylation pathway as paramount in KRAS membrane association, reveals a regulator of prenyltransferase expression, and suggests that reduction in FNTA expression may enhance the efficacy of FTIs.
PMID: 33257571
ISSN: 1091-6490
CID: 4694022

Selective alanine transporter utilization creates a targetable metabolic niche in pancreatic cancer

Parker, Seth J; Amendola, Caroline R; Hollinshead, Kate E R; Yu, Qijia; Yamamoto, Keisuke; Encarnacion-Rosado, Joel; Rose, Rebecca E; LaRue, Madeleine M; Sohn, Albert S W; Biancur, Doug E; Paulo, Joao A; Gygi, Steven P; Jones, Drew R; Wang, Huamin; Philips, Mark R; Bar-Sagi, Dafna; Mancias, Joseph D; Kimmelman, Alec C
Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSCs). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine crosstalk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporter(s) to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer.
PMID: 32341021
ISSN: 2159-8290
CID: 4412012

SAP interacts with CD28 to inhibit PD-1 signaling in T lymphocytes

Sandigursky, Sabina; Philips, Mark; Mor, Adam
T cell co-stimulation is important for the maintenance of immunologic tolerance. Co-inhibitory receptors including programmed cell death-1 (PD-1) confer peripheral tolerance to prevent autoimmunity. SAP (SH2D1A) is an adaptor molecule that is important in T cell signaling and has been shown to interact with signaling lymphocytic activation molecule (SLAM) family receptors also in the context of self-tolerance. We recently reported that SAP interferes with PD-1 function. In the current study, we investigated the levels of SAP and PD-1 in patients with rheumatoid arthritis (RA) to further understand what role they play in disease activity. We observed increased SAP levels in lymphocytes of RA patients and found that PD-1 levels correlated positively with RA disease activity. Additionally, we found that SAP interacts with CD28 to inhibit T cell signaling in vitro. This work demonstrates a putative molecular mechanism for SAP mediated PD-1 inhibition.
PMID: 32504780
ISSN: 1521-7035
CID: 4477622

KRAS4A directly regulates hexokinase 1

Amendola, Caroline R; Mahaffey, James P; Parker, Seth J; Ahearn, Ian M; Chen, Wei-Ching; Zhou, Mo; Court, Helen; Shi, Jie; Mendoza, Sebastian L; Morten, Michael J; Rothenberg, Eli; Gottlieb, Eyal; Wadghiri, Youssef Z; Possemato, Richard; Hubbard, Stevan R; Balmain, Allan; Kimmelman, Alec C; Philips, Mark R
The most frequently mutated oncogene in cancer is KRAS, which uses alternative fourth exons to generate two gene products (KRAS4A and KRAS4B) that differ only in their C-terminal membrane-targeting region1. Because oncogenic mutations occur in exons 2 or 3, two constitutively active KRAS proteins-each capable of transforming cells-are encoded when KRAS is activated by mutation2. No functional distinctions among the splice variants have so far been established. Oncogenic KRAS alters the metabolism of tumour cells3 in several ways, including increased glucose uptake and glycolysis even in the presence of abundant oxygen4 (the Warburg effect). Whereas these metabolic effects of oncogenic KRAS have been explained by transcriptional upregulation of glucose transporters and glycolytic enzymes3-5, it is not known whether there is direct regulation of metabolic enzymes. Here we report a direct, GTP-dependent interaction between KRAS4A and hexokinase 1 (HK1) that alters the activity of the kinase, and thereby establish that HK1 is an effector of KRAS4A. This interaction is unique to KRAS4A because the palmitoylation-depalmitoylation cycle of this RAS isoform enables colocalization with HK1 on the outer mitochondrial membrane. The expression of KRAS4A in cancer may drive unique metabolic vulnerabilities that can be exploited therapeutically.
PMID: 31827279
ISSN: 1476-4687
CID: 4234582

A tribute to Gerald Weissmann (1930-2019)

Abramson, Steven B; Anderson, Paul J; Buyon, Jill P; Cronstein, Bruce N; Pederson, Thoru; Philips, Mark R; Serhan, Charles N
PMID: 31589163
ISSN: 1558-8238
CID: 4129262

A Potent Isoprenylcysteine Carboxylmethyltransferase (ICMT) Inhibitor Improves Survival in Ras-Driven Acute Myeloid Leukemia

Marín-Ramos, Nagore I; Balabasquer, Moisés; Ortega-Nogales, Francisco J; Torrecillas, Iván R; Gil-Ordóñez, Ana; Marcos-Ramiro, Beatriz; Aguilar-Garrido, Pedro; Cushman, Ian; Romero, Antonio; Medrano, Francisco J; Gajate, Consuelo; Mollinedo, Faustino; Philips, Mark R; Campillo, Mercedes; Gallardo, Miguel; Martín-Fontecha, Mar; López-Rodríguez, María L; Ortega-Gutiérrez, Silvia
Blockade of Ras activity by inhibiting its post-translational methylation catalyzed by isoprenylcysteine carboxylmethyltransferase (ICMT) has been suggested as a promising antitumor strategy. However, the paucity of inhibitors has precluded the clinical validation of this approach. In this work we report a potent ICMT inhibitor, compound 3 [UCM-1336, IC50 = 2 μM], which is selective against the other enzymes involved in the post-translational modifications of Ras. Compound 3 significantly impairs the membrane association of the four Ras isoforms, leading to a decrease of Ras activity and to inhibition of Ras downstream signaling pathways. In addition, it induces cell death in a variety of Ras-mutated tumor cell lines and increases survival in an in vivo model of acute myeloid leukemia. Because ICMT inhibition impairs the activity of the four Ras isoforms regardless of its activating mutation, compound 3 surmounts many of the common limitations of available Ras inhibitors described so far. In addition, these results validate ICMT as a valuable target for the treatment of Ras-driven tumors.
PMID: 31181882
ISSN: 1520-4804
CID: 3990642

GGTase3 is a newly identified geranylgeranyltransferase targeting a ubiquitin ligase

Kuchay, Shafi; Wang, Hui; Marzio, Antonio; Jain, Kunj; Homer, Harrison; Fehrenbacher, Nicole; Philips, Mark R; Zheng, Ning; Pagano, Michele
Protein prenylation is believed to be catalyzed by three heterodimeric enzymes: FTase, GGTase1 and GGTase2. Here we report the identification of a previously unknown human prenyltransferase complex consisting of an orphan prenyltransferase α-subunit, PTAR1, and the catalytic β-subunit of GGTase2, RabGGTB. This enzyme, which we named GGTase3, geranylgeranylates FBXL2 to allow its localization at cell membranes, where this ubiquitin ligase mediates the polyubiquitylation of membrane-anchored proteins. In cells, FBXL2 is specifically recognized by GGTase3 despite having a typical carboxy-terminal CaaX prenylation motif that is predicted to be recognized by GGTase1. Our crystal structure analysis of the full-length GGTase3-FBXL2-SKP1 complex reveals an extensive multivalent interface specifically formed between the leucine-rich repeat domain of FBXL2 and PTAR1, which unmasks the structural basis of the substrate-enzyme specificity. By uncovering a missing prenyltransferase and its unique mode of substrate recognition, our findings call for a revision of the 'prenylation code'.
PMID: 31209342
ISSN: 1545-9985
CID: 3939022