Responses to the Strengths and Difficulties Questionnaire predict HbA1c trajectories in children and adolescents with type 1 diabetes: a population-based study.

INTRODUCTION: We aimed to determine whether caregiver responses to the Strengths and Difficulties Questionnaire (SDQ) are predictive of HbA1c trajectory membership in children and adolescents with type 1 diabetes, when adjusting for covariates. RESEARCH DESIGN AND METHODS: For a Danish 2009 national cohort of children and adolescents with type 1 diabetes, we analyzed yearly HbA1c follow-up data during 2010-2020 including sociodemographic data from Danish national registries. Using group-based trajectory modeling and multinomial logistic regression, we tested whether caregiver SDQ scores predicted HbA1c trajectory membership when adjusting for sex, age at diabetes diagnosis, diabetes duration, family structure, and caregiver education. RESULTS: In total, 835 children and adolescents (52% females) with a mean (SD) age of 12.5 (3.3) years, and a mean diabetes duration of 5.2 (3.1) years, were included. Based on 7247 HbA1c observations, four HbA1c trajectories were identified: (1) 'on target, gradual decrease' (26%), (2) 'above target, mild increase then decrease' (41%), (3) 'above target, moderate increase then decrease' (24%), and (4) 'well above target, large increase then decrease' (9%). Higher SDQ total difficulties scores predicted trajectories 3 and 4 (p=0.0002 and p<0.0001, respectively). Regarding the SDQ subscale scores, emotional symptoms predicted trajectories 3 and 4, and conduct problems and hyperactivity/inattention predicted trajectories 2, 3, and 4. Single-parent family and low caregiver education level both predicted trajectories 3 and 4. CONCLUSIONS: Caregiver SDQ responses and sociodemographic information may help detect children and adolescents with type 1 diabetes, who need intensive multidisciplinary medical and psychological interventions.

Associations between disordered eating behaviors and HbA1c in young people with type 1 diabetes: a systematic review and meta-analysis.

BACKGROUND: In type 1 diabetes, disordered eating behaviors (DEBs) can adversely impact HbA1c. Diabetes-adapted DEB questionnaires assess intentional insulin omission, whereas generic questionnaires do not. Given the number of studies describing DEB-HbA1c associations published over the past decade, an updated systematic review is warranted. OBJECTIVE: The study aimed to examine the associations between disordered eating behaviors (DEBs) assessed by generic and diabetes-adapted questionnaires (and subscales) and HbA1c among young people (<29 years) with type 1 diabetes. METHODS: A systematic search was conducted in PubMed, Embase, PsycInfo, and CINAHL databases. Observational studies examining associations between DEB as assessed by questionnaires and HbA1c were included. Publication information, DEB and HbA1c characteristics, and DEB-HbA1c associations were extracted. Hedges' g was calculated for mean HbA1c differences between groups with and without DEB. RESULTS: The systematic search yielded 733 reports, of which 39 reports representing 35 unique studies met the inclusion criteria. Nineteen studies assessing DEB by diabetes-adapted questionnaires (n=5,795) and seven using generic questionnaires (n=2,162) provided data for meta-analysis. For diabetes-adapted questionnaires, DEB was associated with higher HbA1c (g=0.62 CI=0.52; 0.73) with a similar effect size when restricted to validated questionnaires (g=0.61; CI=0.50; 0.73). DEB was not associated with HbA1c for generic questionnaires (g=0.19; CI=-0.17; 0.55), but significantly associated with higher HbA1c for validated generic questionnaires (g=0.32; 95% CI=0.16-0.48). Participant and HbA1c collection characteristics were often inadequately described. CONCLUSION: Diabetes-adapted DEB questionnaires should be used in youth with type 1 diabetes because they capture intentional insulin omission and are more strongly associated with HbA1c than generic DEB questionnaires.

Adherence in Diabetes Questionnaire (ADQ) score as predictor of 11-year HbA1c trajectories in children and adolescents with type 1 diabetes: A population-based longitudinal study.

AIMS: To identify 11-year HbA1c trajectories in children/adolescents with type 1 diabetes and determine whether baseline caregiver- and/or child/adolescent-reported Adherence in Diabetes Questionnaire (ADQ) scores and multiple covariates predict HbA1c trajectory membership. METHODS: For a 2009 population-based cohort of children/adolescents with type 1 diabetes, we analyzed HbA1c follow-up (2010-2020) data from Danish diabetes registries. HbA1c trajectories were identified with group-based trajectory modeling. Using multinomial logistic regression, we tested whether ADQ scores predicted trajectory membership when adjusting for sex, age at diabetes diagnosis, diabetes duration, family structure, and caregiver education. RESULTS: For 671 children/adolescents (10-17 years at baseline) with 5644 HbA1c observations over 11 years, four trajectories/groups were identified: 1) "on target, gradual decrease" (27%), 2) "above target, mild increase then decrease" (39%), 3) "above target, moderate increase then decrease" (25%), and 4) "well above target, large increase then decrease" (9%). Using group one as the reference, lower caregiver-reported ADQ scores predicted group 2, 3, and 4 membership. Lower child/adolescent-reported ADQ scores predicted group 3 and 4 membership. Low caregiver education predicted group 3 and 4 membership. Single-parent status predicted group 4 membership. CONCLUSIONS: ADQ scores and socio-demographics may serve as tools to predict glycemic control in youth with type 1 diabetes.

Leveraging Structure-Based Drug Design to Identify Next-Generation MAT2A Inhibitors, Including Brain-Penetrant and Peripherally Efficacious Leads.

Inhibition of the S-adenosyl methionine (SAM)-producing metabolic enzyme, methionine adenosyltransferase 2A (MAT2A), has received significant interest in the field of medicinal chemistry due to its implication as a synthetic lethal target in cancers with the deletion of the methylthioadenosine phosphorylase (MTAP) gene. Here, we report the identification of novel MAT2A inhibitors with distinct in vivo properties that may enhance their utility in treating patients. Following a high-throughput screening, we successfully applied the structure-based design lessons from our first-in-class MAT2A inhibitor, AG-270, to rapidly redesign and optimize our initial hit into two new lead compounds: a brain-penetrant compound, AGI-41998, and a potent, but limited brain-penetrant compound, AGI-43192. We hope that the identification and first disclosure of brain-penetrant MAT2A inhibitors will create new opportunities to explore the potential therapeutic effects of SAM modulation in the central nervous system (CNS).

Overeating, binge eating, quality of life, emotional difficulties, and HbA1c in adolescents with type 1 diabetes: A Danish national survey.

AIMS: To determine 1) the prevalence of symptoms of overeating (OE), subclinical binge eating (SBE) and clinical binge eating (CBE), in adolescents with type 1 diabetes (T1D), and 2) their associations with quality of life (QoL), anxiety, depression, HbA1c, and body mass index standard deviation score (BMISDS). METHODS: In total 506 adolescents (age 12-17 years; mean 14.7 years; girls 49%) from the Danish Registry for Diabetes in Childhood and Adolescence (DanDiabKids) were included. Participants completed questionnaires on disordered eating, QoL, and emotional difficulties. A blood sample was sent for HbA1c determination. BMISDS was determined from the DanDiabKids data. RESULTS: Prevalence rates of OE, SBE, and CBE were 8.4%, 18% and 7.9% respectively. Youth with CBE symptoms scored lowest on generic and diabetes specific QoL, highest on anxiety and depression symptoms, and had a higher HbA1c. Youth with CBE had borderline increased BMISDS. CONCLUSIONS: In a Danish national survey of adolescents with T1D, approximately one-third of participants had overeating or binge eating symptoms, comparable with the numbers in a U.S T2D population. Increased binge eating symptoms associated with lower QoL, higher depression scores, higher anxiety scores, and poorer clinical outcomes. Binge eating symptoms were markers for poor mental and somatic health.

Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion.

The metabolic enzyme methionine adenosyltransferase 2A (MAT2A) was recently implicated as a synthetic lethal target in cancers with deletion of the methylthioadenosine phosphorylase (MTAP) gene, which is adjacent to the CDKN2A tumor suppressor and codeleted with CDKN2A in approximately 15% of all cancers. Previous attempts to target MAT2A with small-molecule inhibitors identified cellular adaptations that blunted their efficacy. Here, we report the discovery of highly potent, selective, orally bioavailable MAT2A inhibitors that overcome these challenges. Fragment screening followed by iterative structure-guided design enabled >10 000-fold improvement in potency of a family of allosteric MAT2A inhibitors that are substrate noncompetitive and inhibit release of the product, S-adenosyl methionine (SAM), from the enzyme's active site. We demonstrate that potent MAT2A inhibitors substantially reduce SAM levels in cancer cells and selectively block proliferation of MTAP-null cells both in tissue culture and xenograft tumors. These data supported progressing AG-270 into current clinical studies (ClinicalTrials.gov NCT03435250).

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage.

The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.

Selective Vulnerability to Pyrimidine Starvation in Hematologic Malignancies Revealed by AG-636, a Novel Clinical-Stage Inhibitor of Dihydroorotate Dehydrogenase.

Agents targeting metabolic pathways form the backbone of standard oncology treatments, though a better understanding of differential metabolic dependencies could instruct more rationale-based therapeutic approaches. We performed a chemical biology screen that revealed a strong enrichment in sensitivity to a novel dihydroorotate dehydrogenase (DHODH) inhibitor, AG-636, in cancer cell lines of hematologic versus solid tumor origin. Differential AG-636 activity translated to the in vivo setting, with complete tumor regression observed in a lymphoma model. Dissection of the relationship between uridine availability and response to AG-636 revealed a divergent ability of lymphoma and solid tumor cell lines to survive and grow in the setting of depleted extracellular uridine and DHODH inhibition. Metabolic characterization paired with unbiased functional genomic and proteomic screens pointed to adaptive mechanisms to cope with nucleotide stress as contributing to response to AG-636. These findings support targeting of DHODH in lymphoma and other hematologic malignancies and suggest combination strategies aimed at interfering with DNA-damage response pathways.

Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML.

Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG-restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839.

A chemical biology screen identifies a vulnerability of neuroendocrine cancer cells to SQLE inhibition.

Aberrant metabolism of cancer cells is well appreciated, but the identification of cancer subsets with specific metabolic vulnerabilities remains challenging. We conducted a chemical biology screen and identified a subset of neuroendocrine tumors displaying a striking pattern of sensitivity to inhibition of the cholesterol biosynthetic pathway enzyme squalene epoxidase (SQLE). Using a variety of orthogonal approaches, we demonstrate that sensitivity to SQLE inhibition results not from cholesterol biosynthesis pathway inhibition, but rather surprisingly from the specific and toxic accumulation of the SQLE substrate, squalene. These findings highlight SQLE as a potential therapeutic target in a subset of neuroendocrine tumors, particularly small cell lung cancers.

Comparative use of the Ages and Stages Questionnaires in the USA and Scandinavia: a systematic review.

AIM: The aim of this systematic review was to investigate screening practices with the Ages and Stages Questionnaires (ASQ) and the Ages and Stages Questionnaires: Social-Emotional (ASQ:SE) in the USA and Scandinavia and to identify practical lessons and research opportunities. METHOD: The review was performed for ASQ- and ASQ:SE-related studies in children from birth to 5 years. From nine databases and 1689 references (published from 1988-2018), 127 articles were included and categorized using Covidence online software. The Critical Appraisal Skills Programme Checklists were used before data synthesis. RESULTS: US studies primarily use the ASQ/ASQ:SE to detect delays in general and at-risk populations in medical settings, which increases early detection, clinician-referral, and intervention rates. Scandinavian studies commonly use the ASQ/ASQ:SE to monitor developmental-behavioural differences in intervention/exposure-based cohorts. Pre-visit screening yields completion/return rates of 83% to more than 90% and fosters same-day interpretation. When referrals are indicated, systemwide care coordination or colocation with a developmental-behavioural specialist is beneficial. INTERPRETATION: Practical implementation lessons are reviewed. Research opportunities include investigating and measuring the ASQ/ASQ:SE's 'overall' sections. Danish, Norwegian, and Swedish translations are available but up-to-date norming and validation studies are needed throughout Scandinavia. Randomized controlled trials are needed to investigate outcomes in screened versus unscreened cohorts. WHAT THIS PAPER ADDS: General and at-risk populations broadly benefited from periodic Ages and Stages Questionnaires (ASQ) and/or Ages and Stages Questionnaires: Social-Emotional (ASQ:SE) screening. Pre-visit ASQ and/or ASQ:SE screenining implementation systems work best. The ASQ and ASQ:SE 'overall' sections are not quantifiable and under-researched.

USO COMPARATIVO DE LOS CUESTIONARIOS DE EDADES Y ETAPAS EN LOS ESTADOS UNIDOS Y ESCANDINAVIA: UNA REVISIÓN SISTEMÁTICA: OBJETIVO: El objetivo de esta revisión sistemática fue investigar las prácticas de detección con los Cuestionarios de Edades y Etapas (ASQ) y los Cuestionarios de Edades y Etapas: Social-Emocional (ASQ-SE) en EE. UU. y Escandinavia e identificar lecciones prácticas y oportunidades de investigación. MÉTODO: La revisión se realizó para estudios relacionados con ASQ y ASQ-SE SE en niños desde el nacimiento hasta los 5 años. De nueve bases de datos y 1.689 referencias (publicadas entre 1.988 y 2.018), se incluyeron 127 artículos y se categorizaron utilizando el software en línea Covidence. Las listas de verificación del Programa de Habilidades de Evaluación Crítica se usaron antes de la síntesis de datos. RESULTADOS: Los estudios de EE. UU. principalmente usan ASQ / ASQ-SE para detectar retrasos en poblaciones generales y en riesgo en entornos médicos, lo que aumenta la detección temprana, la referencia de los médicos y las tasas de intervención. Los estudios escandinavos utilizan comúnmente el ASQ / ASQ-SE para monitorear las diferencias de desarrollo y comportamiento en las cohortes basadas en intervención / exposición. El tamizaje previo a la visita (pre-screening) arroja tasas de finalización / retorno del 83% a más del 90%, y favorece la interpretación de los resultados en el mismo día. Cuando se indican derivaciones o interconsultas esta información es beneficiosa, para la coordinación a nivel de sistema de atención o la asignación de un especialista en neurodesarrollo y el comportamiento. INTERPRETACIÓN: Revisamos las lecciones prácticas de implementación. Las oportunidades de investigación incluyen investigar y medir las secciones 'generales' de ASQ / ASQ-SE. Las traducciones en danés, noruego y sueco están disponibles, pero se necesitan estudios actualizados de normalización y validación en toda Escandinavia. Se necesitan ensayos controlados aleatorios para investigar los resultados en cohortes tamizadas versus no tamizadas (pre-screening).

USO COMPARATIVO DOS QUESTIONÁRIOS IDADES E ESTÁGIOS NOS EUA E NA ESCANDINÁVIA: UMA REVISÃO SISTEMÁTICA: OBJETIVO: O objetivo desta revisão sistemática foi investigar as práticas de avaliação com os Questionários Idades e Estágios (QIE) e os Questionários Idades e Estágios: Social-emocional (QIE:SE) nos EUA e na Escandinávia, e identificar lições práticas e oportunidades para pesquisas. MÉTODO: A revisão foi realizada para estudos relacionados ao QIE e QIE:SE em crianças do nascimento aos 5 anos de idade. A partir de nove bases de dados e 1689 referências (publicadas de 1988 a 2018), 127 artigos foram incluídos e categorizados usando o software online Covidence. As listsa do Programa de Habilidades de Avaliação Crítica foram aplicadas antes da síntese de dados. RESULTADOS: Estudos americanos primariamente usam o QIE/QIE:SE para detectar atrasos na população geral e de risco em ambientes médicos, o que aumenta a detecção precoce, encaminhamentos clínicos e intervenções. Estudos escandinavos comumente usam o QIE/QIE:SE para monitorar diferenças desenvolvimentais-comportamentais em coortes de intervenção ou que tiveram alguma exposição. Avaliações pré-visita permitem taxas de finalização/retorno de 83% a mais de 90%, e fomenta a interpretação no mesmo dia. Quando encaminhamentos são indicados, a coordenação do cuidado no sistema com um especialista desenvolvimental-comportamental é benéfica. INTERPRETAÇÃO: Lições para implementação prática são revisadas. Oportunidades de pesquisas incluem investigar e medir as seções gerais do QIE/QIE:SE. As traduções para dinamarquês, norueguês e sueco estão disponíveis, mas estudos atuais de normatização e validação são necessários em toda a Escandinávia. Estudos clínicos randomizados são necessários para investigar os desfechos de coortes avaliadas versus não avaliadas.

Comparative use of the Ages and Stages Questionnaires in low- and middle-income countries.

AIM: To map the breadth of use of the Ages and Stages Questionnaires (ASQ) in low- and middle-income countries (LMICs) across world regions, and examine procedures for ASQ translation, adaptation, psychometric evaluation, and administration. METHOD: We conducted a review of all original, peer-reviewed studies written in English referencing use of the ASQ in LMICs. We used a consensus rating procedure to classify each article into one of four categories: feasibility study, psychometric study, prevalence study, or research study. RESULTS: We analysed 53 peer-reviewed articles written in English detailing use of the ASQ in LMICs. We found evidence of ASQ use in 23 LMICs distributed across all world regions. The ASQ was translated into 16 languages. Just over half of the studies reported parent completion of the ASQ (50.9%). We identified eight feasibility studies, 12 psychometric studies, and nine prevalence studies. Study type varied by economy and region. INTERPRETATION: Findings suggest broad global use of the ASQ in a range of countries and cultural and linguistic contexts. There is need for further validation studies across all cited regions and countries and in countries ready to begin to design systems for providing universal developmental screening services. WHAT THIS PAPER ADDS: The Ages and Stages Questionnaires (ASQ) has been used in at least 23 low- and middle-income countries (LMICs). The ASQ has been translated into at least 16 languages in LMICs. Over half the identified studies reported parent completion of the ASQ.

Future Directions of Training and Fieldwork in Diversity Issues in Applied Behavior Analysis.

This paper examines the perceptions of behavior-analytic professionals holding credentials through the Behavior Analyst Certification Board® (BACB®)-including Board Certified Behavior Analysts-Doctoral™, Board Certified Behavior Analysts®, and Board Certified Assistant Behavior Analysts®-regarding multiculturalism and diversity issues in their graduate training, fieldwork, and supervision. This paper predominantly focuses on future directions for improving graduate training, fieldwork, and supervision requirements in the field of applied behavior analysis (ABA) to produce more culturally competent professionals. Results from a preliminary survey of BACB® certificants (N = 575) are included to provide a context for recommendations on how to move the field of ABA forward to enhance the training and preparation of future credentialed professionals.

MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis.

Homozygous deletions of p16/CDKN2A are prevalent in cancer, and these mutations commonly involve co-deletion of adjacent genes, including methylthioadenosine phosphorylase (MTAP). Here, we used shRNA screening and identified the metabolic enzyme, methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. Metabolomic and biochemical studies revealed a mechanistic basis for this synthetic lethality. The MTAP substrate methylthioadenosine (MTA) accumulates upon MTAP loss. Biochemical profiling of a methyltransferase enzyme panel revealed that MTA is a potent and selective inhibitor of PRMT5. MTAP-deleted cells have reduced PRMT5 methylation activity and increased sensitivity to PRMT5 depletion. MAT2A produces the PRMT5 substrate S-adenosylmethionine (SAM), and MAT2A depletion reduces growth and PRMT5 methylation activity selectively in MTAP-deleted cells. Furthermore, this vulnerability extends to PRMT5 co-complex proteins such as RIOK1. Thus, the unique biochemical features of PRMT5 create an axis of targets vulnerable in CDKN2A/MTAP-deleted cancers.

Fluoroquinolone-gyrase-DNA complexes: two modes of drug binding.

DNA gyrase and topoisomerase IV control bacterial DNA topology by breaking DNA, passing duplex DNA through the break, and then resealing the break. This process is subject to reversible corruption by fluoroquinolones, antibacterials that form drug-enzyme-DNA complexes in which the DNA is broken. The complexes, called cleaved complexes because of the presence of DNA breaks, have been crystallized and found to have the fluoroquinolone C-7 ring system facing the GyrB/ParE subunits. As expected from x-ray crystallography, a thiol-reactive, C-7-modified chloroacetyl derivative of ciprofloxacin (Cip-AcCl) formed cross-linked cleaved complexes with mutant GyrB-Cys(466) gyrase as evidenced by resistance to reversal by both EDTA and thermal treatments. Surprisingly, cross-linking was also readily seen with complexes formed by mutant GyrA-G81C gyrase, thereby revealing a novel drug-gyrase interaction not observed in crystal structures. The cross-link between fluoroquinolone and GyrA-G81C gyrase correlated with exceptional bacteriostatic activity for Cip-AcCl with a quinolone-resistant GyrA-G81C variant of Escherichia coli and its Mycobacterium smegmatis equivalent (GyrA-G89C). Cip-AcCl-mediated, irreversible inhibition of DNA replication provided further evidence for a GyrA-drug cross-link. Collectively these data establish the existence of interactions between the fluoroquinolone C-7 ring and both GyrA and GyrB. Because the GyrA-Gly(81) and GyrB-Glu(466) residues are far apart (17 Å) in the crystal structure of cleaved complexes, two modes of quinolone binding must exist. The presence of two binding modes raises the possibility that multiple quinolone-enzyme-DNA complexes can form, a discovery that opens new avenues for exploring and exploiting relationships between drug structure and activity with type II DNA topoisomerases.

Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer.

The LKB1/STK11 tumor suppressor encodes a serine/threonine kinase, which coordinates cell growth, polarity, motility, and metabolism. In non-small cell lung carcinoma, LKB1 is somatically inactivated in 25% to 30% of cases, often concurrently with activating KRAS mutations. Here, we used an integrative approach to define novel therapeutic targets in KRAS-driven LKB1-mutant lung cancers. High-throughput RNA interference screens in lung cancer cell lines from genetically engineered mouse models driven by activated KRAS with or without coincident Lkb1 deletion led to the identification of Dtymk, encoding deoxythymidylate kinase (DTYMK), which catalyzes dTTP biosynthesis, as synthetically lethal with Lkb1 deficiency in mouse and human lung cancer lines. Global metabolite profiling showed that Lkb1-null cells had a striking decrease in multiple nucleotide metabolites as compared with the Lkb1-wild-type cells. Thus, LKB1-mutant lung cancers have deficits in nucleotide metabolism that confer hypersensitivity to DTYMK inhibition, suggesting that DTYMK is a potential therapeutic target in this aggressive subset of tumors.