tbuckley/cabot-search huggingface dataset:
The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes
Authors: Bon Ham Yip, Violetta Steeples, Emmanouela Repapi, Richard N. Armstrong, Miriam Llorian, Swagata Roy, Jacqueline Shaw, Hamid Dolatshad, Stephen Taylor, Amit Verma, Matthias Bartenstein, Paresh Vyas, Nicholas C.P. Cross, Luca Malcovati, Mario Cazzola, Eva Hellström-Lindberg, Seishi Ogawa, Christopher W.J. Smith, Andrea Pellagatti, Jacqueline Boultwood
Journal: Journal of Clinical Investigation (2017)

Mutations of the splicing factor-encoding gene U2AF1 are frequent in the myelodysplastic syndromes (MDS), a myeloid malignancy, and other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and an increasing percentage of bone marrow myeloblasts. We studied the impact of the common U2AF1S34F mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1S34F expression in human hematopoietic progenitors impairs erythroid differentiation and skews granulomonocytic differentiation toward granulocytes. RNA sequencing of erythroid and granulomonocytic colonies revealed that U2AF1S34F induced a higher number of cassette exon splicing events in granulomonocytic cells than in erythroid cells. U2AF1S34F altered mRNA splicing of many transcripts that were expressed in both cell types in a lineage-specific manner. In hematopoietic progenitors, the introduction of isoform changes identified in the U2AF1S34F target genes H2AFY, encoding an H2A histone variant, and STRAP, encoding serine/threonine kinase receptor-associated protein, recapitulated phenotypes associated with U2AF1S34F expression in erythroid and granulomonocytic cells, suggesting a causal link. Furthermore, we showed that isoform modulation of H2AFY and STRAP rescues the erythroid differentiation defect in U2AF1S34F MDS cells, suggesting that splicing modulators could be used therapeutically. These data have critical implications for understanding MDS phenotypic heterogeneity and support the development of therapies targeting splicing abnormalities.
The Cost of Hope: A Candid Roundtable Discussion
Authors: Amanda Bennett, Ronald M. Bukowski, Keith Flaherty, J. Cameron Muir, Craig D. Turner, Sam Donaldson
Journal: Journal of the National Comprehensive Cancer Network (2013)

For Amanda Bennett and her husband Terence Foley, a 7-year battle with kidney cancer resulted in a price tag of more than $600,000, most of it spent in the final 2 years of his life. Ms. Bennett's memoir, The Cost of Hope, chronicles the couple's emotional struggle and the financial irrationality she uncovered when navigating the cancer continuum. She shared her experience in her keynote address at the NCCN 18th Annual Conference, which was followed by a roundtable discussion in which panelists discussed the difficulties inherent in dealing with cancer "uncertainties," the balancing act that seeks to maintain hope in the context of a poor prognosis, and the problem of a health care system that spends too much on some aspects of care while ignoring others.
Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency
Authors: Roberto Alfonso-Dunn, Anne-Marie W. Turner, Pierre M. Jean Beltran, Jesse H. Arbuckle, Hanna G. Budayeva, Ileana M. Cristea, Thomas M. Kristie
Journal: Cell Host & Microbe (2017)
Development of the SaFETy Score: A Clinical Screening Tool for Predicting Future Firearm Violence Risk
Authors: Jason E. Goldstick, Patrick M. Carter, Maureen A. Walton, Linda L. Dahlberg, Steven A. Sumner, Marc A. Zimmerman, Rebecca M. Cunningham
Journal: Annals of Internal Medicine (2017)

Interpersonal firearm violence among youth is a substantial public health problem, and emergency department (ED) physicians require a clinical screening tool to identify high-risk youth.To derive a clinically feasible risk index for firearm violence.24-month prospective cohort study.Urban, level 1 ED.Substance-using youths, aged 14 to 24 years, seeking ED care for an assault-related injury and a proportionately sampled group of non-assault-injured youth enrolled from September 2009 through December 2011.Firearm violence (victimization/perpetration) and validated questionnaire items.A total of 599 youths were enrolled, and presence/absence of future firearm violence during follow-up could be ascertained in 483 (52.2% were positive). The sample was randomly split into training (75%) and post-score-construction validation (25%) sets. Using elastic-net penalized logistic regression, 118 baseline predictors were jointly analyzed; the most predictive variables fell predominantly into 4 domains: violence victimization, community exposure, peer influences, and fighting. By selection of 1 item from each domain, the 10-point SaFETy (Serious fighting, Friend weapon carrying, community Environment, and firearm Threats) score was derived. SaFETy was associated with firearm violence in the validation set (odds ratio [OR], 1.47 [95% CI, 1.23 to 1.79]); this association remained (OR, 1.44 [CI, 1.20 to 1.76]) after adjustment for reason for ED visit. In 5 risk strata observed in the training data, firearm violence rates in the validation set were 18.2% (2 of 11), 40.0% (18 of 45), 55.8% (24 of 43), 81.3% (13 of 16), and 100.0% (6 of 6), respectively.The study was conducted in a single ED and involved substance-using youths. SaFETy was not externally validated.The SaFETy score is a 4-item score based on clinically feasible questionnaire items and is associated with firearm violence. Although broader validation is required, SaFETy shows potential to guide resource allocation for prevention of firearm violence.National Institute on Drug Abuse R01024646.
Beyond Mitophagy
Authors: Sarah E. Shires, Richard N. Kitsis, Åsa B. Gustafsson
Journal: Circulation Research (2017)

P arkin is an E3 ubiquitin ligase that mediates mito- chondrial autophagy, or mitophagy, in multiple cell types.Although discovered in the context of Parkinson disease, Parkin is also an important regulator of mitophagy in the heart.In addition, while most current work is focused on the role of Parkin in mitophagy, accumulating evidence suggests that Parkin also impacts cellular physiology and function through additional processes.This Viewpoint discusses current controversies on the functional role of Parkin-mediated mitophagy and emerging evidence that Parkin regulates several additional pathways.Ubiquitylation is a post-translational modification that involves covalently attaching ubiquitin to target proteins. 1The process of ubquitylation requires a series of events including ubiquitin activation, conjugation, and ligation, catalyzed by E1, E2, and E3 enzymes, respectively.Parkin is one of >500 E3 ubiquitin ligases encoded by the human genome that selectively bestows ubiquitin molecules onto particular proteins.One of Parkin's most widely appreciated roles is the ubiquitylation of proteins on the membrane of damaged mitochondria to designate them for clearance via mitophagy.Mitophagy is a selective form of macroautophagy that traffics damaged mitochondria to lysosomes for degradation and serves as a critical mechanism in maintaining the health of the mitochondrial collective in a cell.
Integrated and Long-Term Safety Analysis of Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
Authors: Steven Coutre, John C. Byrd, Peter Hillmen, Jacqueline C. Barrientos, Paul M. Barr, Stephen Devereux, Tadeusz Robak, Thomas J. Kipps, Anna Schuh, Carol Moreno, Richard R. Furman, Jan Burger, Michael O'Dwyer, Paolo Ghia, Rudolph Valentino, Samuel Suzuki, Joi Ninomoto, Danelle F. James, Susan M. O'Brien
Journal: Blood (2016)
Striatopallidal dysfunction underlies repetitive behavior in Shank3-deficient model of autism
Authors: Wenting Wang, Chenchen Li, Qian Chen, Marie-Sophie van der Goes, James Hawrot, Annie Y. Yao, Xian Gao, Congyi Lu, Ying Zang, Qiangge Zhang, Katherine Lyman, Dongqing Wang, Baolin Guo, Shengxi Wu, Charles R. Gerfen, Zhanyan Fu, Guoping Feng
Journal: Journal of Clinical Investigation (2017)

The postsynaptic scaffolding protein SH3 and multiple ankyrin repeat domains 3 (SHANK3) is critical for the development and function of glutamatergic synapses. Disruption of the SHANK3-encoding gene has been strongly implicated as a monogenic cause of autism, and Shank3 mutant mice show repetitive grooming and social interaction deficits. Although basal ganglia dysfunction has been proposed to underlie repetitive behaviors, few studies have provided direct evidence to support this notion and the exact cellular mechanisms remain largely unknown. Here, we utilized the Shank3B mutant mouse model of autism to investigate how Shank3 mutation may differentially affect striatonigral (direct pathway) and striatopallidal (indirect pathway) medium spiny neurons (MSNs) and its relevance to repetitive grooming behavior in Shank3B mutant mice. We found that Shank3 deletion preferentially affects synapses onto striatopallidal MSNs. Striatopallidal MSNs showed profound defects, including alterations in synaptic transmission, synaptic plasticity, and spine density. Importantly, the repetitive grooming behavior was rescued by selectively enhancing the striatopallidal MSN activity via a Gq-coupled human M3 muscarinic receptor (hM3Dq), a type of designer receptors exclusively activated by designer drugs (DREADD). Our findings directly demonstrate the existence of distinct changes between 2 striatal pathways in a mouse model of autism and indicate that the indirect striatal pathway disruption might play a causative role in repetitive behavior of Shank3B mutant mice.
SGN-33 Modulates Cytokine and Chemokine Production by Activated Monocytes and Macrophages.
Authors: May S.K. Sutherland, Timothy S. Lewis, Changpu Yu, Julie A. McEarchern, Jonathan G. Drachman, Eric L. Sievers, Iqbal S. Grewal, Che-Leung Law
Journal: Blood (2006)
Omipalisib (GSK458), a Dual an-PI3K/mTOR Inhibitor, Exhibits in Vitro and In Vivo activity in Chemotherapy-Sensitive and -Resistant Models of Burkitt Lymphoma
Authors: Thomas Ippolito, Cory Mavis, Juan Gu, Francisco J. Hernandez-Ilizaliturri, Matthew J. Barth
Journal: Blood (2018)
Therapy reduction in patients with Down syndrome and myeloid leukemia: the international ML-DS 2006 trial
Authors: Madita Uffmann, Mareike Rasche, Martin Zimmermann, Christine von Neuhoff, Ursula Creutzig, Michael Dworzak, Lenie Scheffers, Henrik Hasle, C. Michel Zwaan, Dirk Reinhardt, Jan-Henning Klusmann
Journal: Blood (2017)
Community Mitigation Guidelines to Prevent Pandemic Influenza — United States, 2017
Authors: Noreen Qualls, Alexandra Levitt, Neha Kanade, Narue Wright-Jegede, Stephanie Dopson, Matthew Biggerstaff, Carrie Reed, Amra Uzicanin, Alexandra Levitt, Stephanie Dopson, Mark Frank, Rachel Holloway, Lisa Koonin, Sonja Rasmussen, Stephen Redd, Christopher de la Motte Hurst, Neha Kanade, Noreen Qualls, Jeanette Rainey, Amra Uzicanin, Matthew Biggerstaff, Daniel Jernigan, Carrie Reed
Journal: MMWR Recommendations and Reports (2017)

This report from CDCâs Morbidity and Mortality Weekly Report (MMWR) replaces the 2007 Interim Pre-pandemic Planning Guidance: Community Strategy for Pandemic Influenza Mitigation in the United States â Early, Targeted, Layered Use of Nonpharmaceutical Interventions.
Worldwide Preparedness for Kidney Health Care
Authors: Sreedhar Mandayam, Wolfgang C. Winkelmayer
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Acquired <i>MET</i> Y1248H and D1246N Mutations Mediate Resistance to MET Inhibitors in Non–Small Cell Lung Cancer
Authors: Anna Li, Jin-ji Yang, Xu-chao Zhang, Zhou Zhang, Jian Su, Lan-ying Gou, Yu Bai, Qing Zhou, Zhenfan Yang, Han Han-Zhang, Wen-Zhao Zhong, Shannon Chuai, Qi Zhang, Zhi Xie, Hongfei Gao, Huajun Chen, Zhen Wang, Zheng Wang, Xue-ning Yang, Bin-chao Wang, Bin Gan, Zhi-hong Chen, Ben-yuan Jiang, Si-pei Wu, Si-yang Liu, Chong-rui Xu, Yi-long Wu
Journal: Clinical Cancer Research (2017)

Purpose:MET amplification, responsible for 20% of acquired resistance to EGFR tyrosine kinase inhibitor (TKI) in patients with advanced non-small cell lung cancer (NSCLC), presents an attractive target. Numerous studies have conferred susceptibility of MET mutations and focal amplification to targeted MET-TKIs. However, the mechanism underlying MET-TKIs-induced resistance remains elusive.Experimental Design: We conducted a cohort of 12 patients with advanced NSCLC who developed resistance to a combinatorial therapy consisting of gefitinib and a type I MET-TKI. We performed capture-based targeted ultra-deep sequencing on serial tumor biopsies and plasmas ctDNA samples to detect and quantify genetic alterations.Results: We identified 2 newly acquired MET mutations, Y1248H and D1246N, in 2 patients and further confirmed their resistance against type I MET-TKIs in silco, in vitro, and in vivo Interestingly, NIH3T3 cells harboring either mutation exhibited responses to type II MET-TKIs, suggesting sequential use of MET-TKIs may offer a more durable response. In addition, we also discovered that EGFR amplification may act as an alternative MET-TKI resistance mechanism.Conclusions: Our study provides insight into the diversity of mechanisms underlying MET-TKI-induced resistance and highlights the potential of sequential use of MET-TKIs. Clin Cancer Res; 23(16); 4929-37. ©2017 AACR.
CMR–Derived Extracellular Volume Fraction as a Marker for Myocardial Fibrosis
Authors: Julia Anna Lurz, Christian Luecke, David Lang, Christian Besler, Karl-Philipp Rommel, Karin Klingel, Reinhard Kandolf, Volker Adams, Katharina Schöne, Gerhard Hindricks, Gerhard Schuler, Axel Linke, Holger Thiele, Matthias Gutberlet, Philipp Lurz
Journal: JACC. Cardiovascular imaging (2017)
Anti-3rd party human ctl's generated from autologous or allogeneic t cells are endowed with potent gvl activity in the absence of gvho
Authors: Fabian D. Arditti, Shraga Aviner, Rita Krauthgamer, Judith Gan, Hilit Gur, Arnon Nagler, Yaniv Yitzchak, Jerry Stein, Jacob Row, Antonio Tabilio, Massimo Martelli, Alain Berrebi, Yair Reisner
Journal: Blood (2000)
Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma
Authors: Laurence H.M. Pierrache, Adva Kimchi, Rinki Ratnapriya, Lisa Roberts, Galuh D.N. Astuti, Alexey Obolensky, Avigail Beryozkin, Martha J.H. Tjon-Fo-Sang, Jose Schuil, Caroline C.W. Klaver, Ernie M.H.F. Bongers, Lonneke Haer-Wigman, Nicoline Schalij, Martijn H. Breuning, Gratia M. Fischer, Eyal Banin, Raj S. Ramesar, Anand Swaroop, L. Ingeborgh van den Born, Dror Sharon, Frans P.M. Cremers
Journal: Ophthalmology (2017)
Easily Performed Functional Flow Cytometry Assay for Heparin-Induced Thrombocytopenia and Thrombosis (HIT): Correlation with Clinical Presentation, Immunoassay and Serotonin-Release Assay
Authors: Michal Cipok, Varda R Deutsch, Ismail Elalamy, Ilya Kirgner, Sigi Kay, Aaron Tomer
Journal: Blood (2016)
A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity
Authors: Kyoung-Jin Chung, Antonios Chatzigeorgiou, Matina Economopoulou, Ruben Garcia-Martin, Vasileia I Alexaki, Ioannis Mitroulis, Marina Nati, Janine Gebler, Tjalf Ziemssen, Susan E Goelz, Julia Phieler, Jong-Hyung Lim, Katia P Karalis, Thalia Papayannopoulou, Matthias Blüher, George Hajishengallis, Triantafyllos Chavakis
Journal: Nature Immunology (2017)
Efficacy of anti-sclerostin monoclonal antibody BPS804 in adult patients with hypophosphatasia
Authors: Lothar Seefried, Jasmin Baumann, Sarah Hemsley, Christine Hofmann, Erdmute Kunstmann, Beate Kiese, Yue Huang, Simon Chivers, Marie-Anne Valentin, Babul Borah, Ronenn Roubenoff, Uwe Junker, Franz Jakob
Journal: Journal of Clinical Investigation (2017)

BACKGROUND. Hypophosphatasia (HPP) is a rare genetic disorder resulting in variable alterations of bone formation and mineralization that are caused by mutations in the ALPL gene, encoding the tissue-nonspecific alkaline phosphatase (ALP) enzyme.
TCTAP A-019 Clinical Impact of D-dimer Level on Admission in Predicting Coronary Slow-flow Phenomenon and In-hospital Major Adverse Cardiac Events in Patients Presenting with ST-segment Elevation Myocardial Infraction
Authors: Yuhei Goriki, Tatsuya Nakama, Yoshisato Shibata
Journal: Journal of the American College of Cardiology (2017)
Lower urinary tract symptoms in an older man
Authors: Maria Vedanayagam, Amit Kumar, Sanjeev Madaan
Journal: BMJ (2017)

#### What you need to know

A 65 year old man comes to see you with problems urinating. He feels the need to pass urine often, and it takes a long time to void when he does.

Lower urinary tract symptoms in men are common and increase with age.1 There is an estimated prevalence of >50% in men over 50 years old.2 Between the ages of 40 and 79 years, the prevalence of moderate to severe symptoms increases by 9.8% per decade.3 There is also a strong association of lower urinary tract symptoms with metabolic syndrome (including obesity, diabetes, and hypertension).45

Lower urinary tract symptoms in men are most commonly due to benign prostatic enlargement, which can cause bladder outflow obstruction.67 However, not all men with benign prostatic enlargement will have bothersome symptoms.6 Lower urinary tract symptoms can interfere with general wellbeing, sleep, and sexual activity. They are an independent risk factor for sexual dysfunction in men over the age of 50 years.2 Some patients who seek medical attention may be …
Implantation of insulin infusion devices
Authors: F. J. Service
Journal: JAMA (1982)

During the past several years, there has been an accumulation of evidence indicating that portable insulin infusion devices have the potential to provide an approximation of normoglycemia in the compliant, insulin-dependent diabetic patient.<sup>1-5</sup>The greatest experience with these devices has been obtained using the subcutaneous route for insulin administration,<sup>1-3</sup>with considerably fewer patients having been given insulin by the peripheral venous<sup>4</sup>and intraperitoneal routes.<sup>5,6</sup>In addition to its effect on blood glucose concentrations, continuous subcutaneous insulin infusion has been reported to normalize or improve peripheral venous concentrations of other substrates (eg, free fatty acids, ketone bodies, and amino acids)<sup>7</sup>and hormones (glucagon and growth hormone) whose levels are often abnormal in patients treated conventionally.<sup>8,9</sup>Whether the flux of substrates and their disposition in specific tissues are comparably affected has not been established. Unfortunately, some serious adverse effects such as severe hypoglycemia<sup>10</sup>and ketoacidosis
Changes in Rates of Ventilator-Associated Pneumonia—Reply
Authors: Mark L. Metersky, Michael Klompas, Noel Eldridge
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Hemorrhagic Cystitis in Haploidentical Hematopoietic STEM CELL Trasplant: Retrospective Study and Comparison with a NON-Haploidentical DONOR Transplant Group
Authors: Nerea Arratibel, Monica Cabrero, Estefania Perez, Oriana Lopez, Lucia Lopez, Ana A. Martin, Alvaro Veiga, Monica Baile, Veronica Gonzalez, Felix Lopez, Oscar Ferre, Luis García, Dolores Caballero, Lourdes Vazquez, Maria-Victoria Mateos
Journal: Blood (2016)
Carcinogenicity of welding, molybdenum trioxide, and indium tin oxide
Authors: Neela Guha, Dana Loomis, Kathryn Z Guyton, Yann Grosse, Fatiha El Ghissassi, Véronique Bouvard, Lamia Benbrahim-Tallaa, Nadia Vilahur, Karen Muller, Kurt Straif
Journal: The Lancet Oncology (2017)
TCTAP C-227 Endovascular Therapy with a Three-dimensional Guidewire Technique for the Treatment of Chronic Total Occlusions of Superficial Femoral Artery
Authors: Akinori Sumiyoshi, Atsunori Okamura, Hiroyuki Nagai, Tomohiro Yamasaki, Takamasa Tanaka
Journal: Journal of the American College of Cardiology (2017)
Lentiviral Vectors with Cellular Promoters Correct Anemia and Lethal Bone Marrow Failure in a Mouse Model for Diamond-Blackfan Anemia
Authors: Shubhranshu Debnath, Pekka Jaako, Kavitha Siva, Michael Rothe, Jun Chen, Maria Dahl, H. Bobby Gaspar, Johan Flygare, Axel Schambach, Stefan Karlsson
Journal: Molecular Therapy (2017)
SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer
Authors: Eiki Ichihara, David Westover, Catherine B. Meador, Yingjun Yan, Joshua A. Bauer, Pengcheng Lu, Fei Ye, Amanda Kulick, Elisa de Stanchina, Robert McEwen, Marc Ladanyi, Darren Cross, William Pao, Christine M. Lovly
Journal: Cancer Research (2017)

Mutant-selective EGFR tyrosine kinase inhibitors (TKI), such as osimertinib, are active agents for the treatment of EGFR-mutant lung cancer. Specifically, these agents can overcome the effects of the T790M mutation, which mediates resistance to first- and second-generation EGFR TKI, and recent clinical trials have documented their efficacy in patients with EGFR-mutant lung cancer. Despite promising results, therapeutic efficacy is limited by the development of acquired resistance. Here we report that Src family kinases (SFK) and focal adhesion kinase (FAK) sustain AKT and MAPK pathway signaling under continuous EGFR inhibition in osimertinib-sensitive cells. Inhibiting either the MAPK pathway or the AKT pathway enhanced the effects of osimertinib. Combined SFK/FAK inhibition exhibited the most potent effects on growth inhibition, induction of apoptosis, and delay of acquired resistance. SFK family member YES1 was amplified in osimertinib-resistant EGFR-mutant tumor cells, the effects of which were overcome by combined treatment with osimertinib and SFK inhibitors. In conclusion, our data suggest that the concomitant inhibition of both SFK/FAK and EGFR may be a promising therapeutic strategy for EGFR-mutant lung cancer. Cancer Res; 77(11); 2990-3000. ©2017 AACR.