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Although the association of smoking with the risk of incident neurological disorders is well established, less is known about the impact of smoking and smoking cessation on outcomes of these conditions. The objective of this scoping review was to synthesize what is known about the impact of smoking and smoking cessation on disease-specific outcomes for seven common neurological disorders. We included 67 studies on the association of smoking and smoking cessation on disease-specific outcomes. For multiple sclerosis, smoking was associated with greater clinical and radiological disease progression, relapses, risk for disease-related death, cognitive decline, and mood symptoms, in addition to reduced treatment effectiveness. For stroke and transient ischemic attack, smoking was associated with greater rates of stroke recurrence, post-stroke cardiovascular outcomes, post-stroke mortality, post-stroke cognitive impairment, and functional impairment. In patients with cognitive impairment and dementia, smoking was associated with faster cognitive decline, and smoking was also associated with greater cognitive decline in Parkinson's disease, but not motor symptom worsening. Patients with amyotrophic lateral sclerosis who smoked faced increased mortality. Last, in patients with cluster headache, smoking was associated with more frequent and longer cluster attack periods. Conversely, for multiple sclerosis and stroke, smoking cessation was associated with improved disease-specific outcomes. In summary, whereas smoking is detrimentally associated with disease-specific outcomes in common neurological conditions, there is growing evidence that smoking cessation may improve outcomes. Effective smoking cessation interventions should be leveraged in the management of common neurological disorders to improve patient outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. N. Parikh has received personal fees for medicolegal consulting and provides blinded end point assessment for the Embolization of the Middle Meningeal Artery with ONYX Liquid Embolic System for Subacute and Chronic Subdural Hematoma trial (Medtronic) for participants enrolled at his institution. Dr. N. Parikh was supported by the NIH/NIA (K23 AG073524) and Florence Gould Endowment for Discovery in Stroke. There are no direct relationships between these interests and the topic of this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Older adults undergoing head and neck cancer (HNC) surgery often have significant functional and mental health impairments. We examined use of postoperative physical, nutritional, and psychosocial services among a cohort of older adults with HNC comanaged by geriatricians and surgeons., Materials and Methods: Our sample consisted of older adults who were referred to the Geriatrics Service at Memorial Sloan Kettering Cancer Center between 2015 and 2019 and took a geriatric assessment (GA) prior to undergoing HNC surgery. Physical, nutritional, and psychosocial service utilization was assessed. Physical services included a physical, occupational, or rehabilitation consult during the patient's stay. Nutritional services consisted of speech and swallow or nutritional consult. Psychosocial services consisted of psychiatry, psychology, or a social work consult. Relationships between each service use, geriatric deficits, demographic, and surgical characteristics were assessed using Wilcoxon rank-sum test or Chi-square test., Results: In total, 157 patients were included, with median age of 80 and length of stay of six days. The most common GA impairments were major distress (61%), depression (59%), social activity limitation (SAL) (54%), and deficits in activities of daily living (ADL) (44%). Nutritional and physical services were used much more frequently than psychosocial services (80% and 85% vs 31%, respectively). Receipt of services was associated with longer median length of hospital stay, operation time, and greater deficits in ADLs. SAL was associated with physical and psychosocial consult and lower Timed Up and Go (TUG) score; instrumental ADL (iADL) deficits were associated with physical services; and depression and distress were associated with psychosocial services., Discussion: The burden of psychosocial deficits is high among older adults with HNC. Future work is needed to understand the limited utilization of psychosocial services in this population as well as whether referral to psychosocial services can reduce the burden of these deficits., Competing Interests: Conflicts of Interest Dr. Lee reports receiving consulting fees from Shanghai JoAnn Medical Technology Co., Ltd., support for meetings and/or travel from Varian, and participation on boards at Merck and Merck Serono. No other authors have anything to report., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways. Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy. Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184., (©2023 American Association for Cancer Research.)

In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels. This raises an unresolved question of how PDAC cells obtain essential metabolites and water-insoluble lipids. We have found a critical role for cancer-associated fibroblasts (CAFs) in obtaining and transferring lipids from blood-borne particles to PDAC cells via trogocytosis of CAF plasma membranes. We have also determined that CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) is an essential CAF trogocytosis regulator required to promote PDAC cell survival. During trogocytosis, cancer cells and CAFs form synapse-like plasma membranes contacts that induce cytosolic calcium influx in CAFs via Orai channels. This influx activates ANO6 and results in phosphatidylserine exposure on CAF plasma membrane initiating trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. Importantly, ANO6-dependent trogocytosis also supports the immunosuppressive function of pancreatic CAFs towards cytotoxic T cells by promoting transfer of excessive amounts of cholesterol. Further, blockade of ANO6 antagonizes tumor growth via disruption of delivery of exogenous cholesterol to cancer cells and reverses immune suppression suggesting a potential new strategy for PDAC therapy.

Background: Smoking cessation rates after stroke and transient ischemic attack are suboptimal, and smoking cessation interventions are underutilized. We performed a cost-effectiveness analysis of smoking cessation interventions in this population., Methods: We constructed a decision tree and used Markov models that aimed to assess the cost-effectiveness of varenicline, any pharmacotherapy with intensive counseling, and monetary incentives, compared with brief counseling alone in the secondary stroke prevention setting. Payer and societal costs of interventions and outcomes were modeled. The outcomes were recurrent stroke, myocardial infarction, and death using a lifetime horizon. Estimates and variance for the base case (35% cessation), costs and effectiveness of interventions, and outcome rates were imputed from the stroke literature. We calculated incremental cost-effectiveness ratios and incremental net monetary benefits. An intervention was considered cost-effective if the incremental cost-effectiveness ratio was less than the willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY) or when the incremental net monetary benefit was positive. Probabilistic Monte Carlo simulations modeled the impact of parameter uncertainty., Results: From the payer perspective, varenicline and pharmacotherapy with intensive counseling were associated with more QALYs (0.67 and 1.00, respectively) at less total lifetime costs compared with brief counseling alone. Monetary incentives were associated with 0.71 more QALYs at an additional cost of $120 compared with brief counseling alone, yielding an incremental cost-effectiveness ratio of $168/QALY. From the societal perspective, all 3 interventions provided more QALYs at less total costs compared with brief counseling alone. In 10 000 Monte Carlo simulations, all 3 smoking cessation interventions were cost-effective in >89% of runs., Conclusions: For secondary stroke prevention, it is cost-effective and potentially cost-saving to deliver smoking cessation therapy beyond brief counseling alone.

People who continue to smoke after ischemic stroke and transient ischemic attack (TIA) are at increased risk for subsequent stroke and cardiovascular events. Although effective smoking cessation strategies exist, smoking rates after stroke remain high. Through case-based discussions with 3 international vascular neurology panelists, this article seeks to explore practice patterns and barriers to smoking cessation for patients with stroke/TIA. We sought to answer these questions: What are the barriers to using smoking cessation interventions for patients with stroke/TIA? Which interventions are most used for hospitalized patients with stroke/TIA? Which interventions are most used for patients who continue smoking during follow-up? Our synthesis of panelists' commentaries is complemented by the preliminary results of an online survey posed to global readership. Together, the interviews and survey results identify practice variability and barriers to smoking cessation after stroke/TIA, suggesting that there is substantial need for research and standardization., (© 2023 American Academy of Neurology.)

Purpose: Treatment patterns for head and neck squamous cell carcinoma (HNSCC) vary among older adults because of concerns about their health status. Geriatric assessment may guide treatment for older adults with HNSCC by assessing their health status., Methods and Materials: We conducted a retrospective review of adjuvant treatment received by older patients with HNSCC who completed a novel geriatric assessment, the electronic Rapid Fitness Assessment, before treatment. The electronic Rapid Fitness Assessment yields an accumulated geriatric deficits (AGD) score. Higher AGD score indicates greater frailty. Comparators were age and performance status. The Wilcoxon rank sum test compared differences between those who did and did not receive adjuvant radiation therapy and chemotherapy., Results: The cohort included 73 patients, of whom 56 (77%) had oral cavity cancer. The most common geriatric deficits were major distress, social activity limitation, depression, and impaired activities of daily living. AGD score, age, and performance status were not associated with receipt of adjuvant radiation. Patients who received adjuvant chemotherapy had a significantly lower median AGD score than those who did not (3 vs 6; P  = .044), but there was no association with age and performance status. Of the 17 patients with newly diagnosed disease and either positive margins or extranodal extension, only 9 received adjuvant radiation and only 3 received systemic therapy. Most often, systemic therapy was omitted because of patient preference or comorbidities and poor performance status. There was a nonstatistically significant lower AGD score between patients who did and did not receive standard fractionated radiation therapy (median, 4 vs 6.5; P  = .13)., Conclusions: Receipt of adjuvant chemotherapy was associated with frailty. Rates of chemotherapy utilization were very low, indicating the need for novel strategies to mitigate the toxicity burden in this patient population. Receipt of adjuvant radiation therapy was not associated with frailty; however, there was a trend toward lower frailty among those who did receive radiation therapy., (© 2022 The Author(s).)

Purpose: Older adults with head and neck cancer have increased postoperative complications, longer hospital stays, and higher rates of mortality. Geriatric assessment (GA) provides a measure of overall health status and is preferable to using age alone for assessing fitness for surgery. We sought to determine whether a patient's frailty as determined by a novel electronic GA is associated with outcomes after head and neck cancer (HNC) surgery., Methods: We conducted a retrospective review of 159 patients aged 75 and older referred to the Geriatrics Service at Memorial Sloan Kettering Cancer Center for pre-operative evaluation prior to undergoing HNC surgery. All patients completed the electronic Rapid Fitness Assessment (eRFA) within 60 days prior to surgery. The accumulated geriatric deficit (AGD) score includes twelve domains from the eRFA with a point assigned for each domain in which there is a deficit and a final point related to comorbidities. Three other metrics were individually assessed: age, Karnofsky Performance Scale (KPS), and number of comorbidities. We utilized multivariable linear regression and t-tests to determine whether frailty is associated with longer length of hospital stay, 30-day intensive care unit (ICU) admission, and 30-day and 90-day postoperative mortality., Results: Patients with a higher AGD score spent more time in the hospital post-operatively (1.0 day increase per unit increase in AGD; 95% CI: 0.21-1.9; p = 0.015). Lower KPS was also associated with statistically significant longer length of stay (-2.70 day change per increasing index KPS; 95% CI: -4.30 - -1.00; days; p = 0.002), while age and comorbidity were not found to be statistically associated with length of stay. Higher AGD score remained significantly associated with longer length of stay on multivariable analysis (0.93 day increase per unit increase in AGD; 95% CI 0.15-1.71; p = 0.019). AGD was the only metric associated with increased risk of ICU admission (6.6 vs 5.0 geriatric deficits for those admitted vs not admitted to ICU; p = 0.024)., Conclusions: Frailty is associated with increased length of hospital stay and ICU admission in older adults with HNC undergoing surgery. GA can be used to counsel patients on the expected postoperative course., Competing Interests: Declaration of Competing Interest The authors have no relevant financial conflicts of interest., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The detrimental impact of tobacco smoking on brain health is well recognized., Objective: To evaluate whether smoking acts synergistically with hypertension and diabetes to influence cognitive performance., Methods: We performed a cross-sectional analysis using the US National Health and Nutrition Examination Survey. Participants were tested for serum cotinine, a validated cigarette smoking/exposure biomarker, and had standardized blood pressure and hemoglobin A1c measurements. Participants were administered four cognitive tests: Digit Symbol Substitution (DSST), Animal Fluency, Immediate Recall, and Delayed Recall. Multivariable linear regression models adjusted for demographics and confounders evaluated the association of cotinine with cognition. Interaction testing evaluated effect modification by hypertension, diabetes, and their continuous measures (systolic blood pressure and hemoglobin A1c)., Results: For 3,007 participants, mean age was 69.4 years; 54% were women. Using cotinine levels, 14.9% of participants were categorized as active smokers. Higher cotinine levels were associated with worse DSST performance when modeling cotinine as a continuous variable (β, -0.70; 95% CI, -1.11, -0.29; p < 0.01) and when categorizing participants as active smokers (β, -5.63; 95% CI, -9.70, -1.56; p < 0.01). Cotinine was not associated with fluency or memory. Effect modification by hypertension and diabetes were absent, except that cotinine was associated with worse Immediate Recall at lower blood pressures., Conclusion: Higher levels of a smoking and secondhand exposure biomarker were associated with worse cognitive performance on a multidomain test. Overall, the relationship of cotinine with cognition was not contingent on or amplified by hypertension or diabetes; smoking is detrimental for brain health irrespective of these comorbidities.

Smoking cessation is critical in secondary prevention after stroke and transient ischemic attack. Data regarding use of smoking-cessation interventions after stroke and transient ischemic attack are sparse. We examined the use of prescription smoking-cessation medications in these patients. This is a retrospective cohort study using 2013-2016 data from the INSIGHT Clinical Research Network, comprised of Medicare prescription claims data merged with electronic health record data for patients receiving care across five New York City health care institutions. Active smoking was ascertained based on a validated ICD-9-CM diagnosis code or the presence of an electronic health record active smoking indicator, reflecting clinician-entered data in the health record. The primary outcome was a claim for any prescription smoking-cessation medication (varenicline or bupropion) within 12 months of hospital discharge. We evaluated claims for any statin medication as a comparator because statins are a standard component of stroke secondary prevention. We identified 3,153 patients with stroke or transient ischemic attack who were active smokers at the time of their event. Among these patients, 3.1% (95% CI, 2.5-3.9) had a pharmacy claim for a prescription smoking-cessation medication at 6 months, and 4.7% (95% CI, 3.9-5.6) did at 12 months hospital discharge. In contrast, cumulative statin medication claims rates were 67.5% (95% CI, 65.5-69.5%) at 6 months and 74.6% (95% CI, 72.7-76.6%) at 12 months. Prescription s moking-cessation medications were infrequently used after stroke and transient ischemic attack., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Parikh has received medicolegal consulting compensation and prior funding from the Leon Levy Foundation unrelated to this work. Dr. Zhang: none. Mr. Restifo: none. Dr. Abramson: none. Dr. Carpenter has previously received consulting honoraria from Pfizer. Dr. Navi has received medicolegal consulting compensation. Dr. Kamel serves as a principal investigator for the NIH-funded ARCADIA trial (National Institute of Neurological Disorders and Stroke U01NS095869) which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis® and ancillary study support from Roche Diagnostics, serves as Deputy Editor for JAMA Neurology, serves as a steering committee member of Medtronic’s Stroke AF trial (uncompensated), and serves on an endpoint adjudication committee for a trial of empagliflozin for Boehringer-Ingelheim., (© 2021 The Authors.)

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1 + cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1 + CAFs are intrinsically immunosuppressive and inhibit natural killer cell-mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC. SIGNIFICANCE: This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function. See related commentary by Sherman, p. 230 . This article is highlighted in the In This Issue feature, p. 211 ., (©2020 American Association for Cancer Research.)

Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by Kras G12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients., Competing Interests: Declaration of Interests I.A. served as a consultant for Caris Life Sciences, Inc., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Diabetes has been identified as a risk factor for developing colorectal cancer (CRC); however, the literature identifying groups most at risk is sparse. This study aims to understand the relationship between CRC and diabetes by age and race/ethnicity., Methods: This is a cross-sectional study of data from the 2001-2014 National Health and Nutrition Examination Survey (unweighted n = 37,173; weighted n = 214,363,348). Individuals were categorized as having CRC if diagnosed with colon or rectal cancer and as having diabetes if told by a doctor they had diabetes, were taking insulin, or had an HbA1c ≥ 6.5%. Covariates included gender, age, race, marital status, educational level and income as a ratio of the poverty line. Multivariable logistic regression was used to assess the relationship between CRC and diabetes overall and stratified by age and by race., Results: 24.32% of the sample with CRC also had diabetes. After adjusting for covariates, individuals with diabetes had a 47% greater probability of having CRC (p = 0.03). While significance did not persist after stratification for those ≥65 years (OR = 1.06, p = 0.74), those <65 years with diabetes had nearly 5-times higher odds of having CRC (OR = 4.78, p < 0.001). When stratified by race, both groups had statistically higher odds of having CRC; however, the odds for non-whites (OR = 1.87, p = 0.04) were higher compared to whites (OR = 1.54, p = 0.03)., Conclusion: Individuals younger than 65 and racial/ethnic minorities have higher odds of CRC when also diagnosed with diabetes. Targeted interventions for these populations, especially regarding screening recommendations, may result in earlier detection of CRC and improved health outcomes., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The lack of effective treatment modalities is a major problem in pancreatic cancer (PCa), a devastating malignancy that is nearly universally driven by the "undruggable" KRAS and TP53 cancer genes. Poor tumor tissue penetration is the major source of resistance in pancreatic cancer where chemotherapy is the mainstay of treatment. In this study we exploited the selective tumor-targeting properties of the heat shock 90 protein inhibitors as the vehicle for drug delivery to pancreatic tumor tissues. STA-12-8666 is a novel esterase-cleavable conjugate of an HSP90i and a topoisomerase I inhibitor, SN-38. STA-12-8666 selectively binds activated HSP90 and releases its cytotoxic payload resulting in drug accumulation in pancreatic cancer cells in vivo. We investigated the preclinical activity of STA-12-8666 in patient derived xenograft and genetic models of pancreatic cancer.Treatment with STA-12-8666 of the KPC mice (knock-in alleles of LSL-KrasG12D, Tp53fl/fl and Pdx1-Cre transgene) at the advanced stages of pancreatic tumors doubled their survival (49 days vs. 74 days, p=0.008). STA-12-8666 also demonstrated dramatically superior activity in comparison to equimolar doses of irinotecan against 5 patient-derived pancreatic adenocarcinoma xenografts with prolonged remissions in some tumors. Analysis of activity of STA-12-8666 against tumor tissues and matched cell lines demonstrated prolonged accumulation and release of cytotoxic payload in the tumor leading to DNA damage response and cell cycle arrest.Our results provide a proof-of-principle validation that HSP90i-based drug conjugates can overcome the notorious treatment resistance by utilizing the inherently high affinity of pancreatic cancer cells to HSP90 antagonists.

Purpose: Even when diagnosed prior to metastasis, pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with almost 90% lethality, emphasizing the need for new therapies optimally targeting the tumors of individual patients., Experimental Design: We first developed a panel of new physiologic models for study of PDAC, expanding surgical PDAC tumor samples in culture using short-term culture and conditional reprogramming with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). These were evaluated for sensitivity to a large panel of clinical agents, and promising leads further evaluated mechanistically., Results: Only a small minority of tested agents was cytotoxic in minimally passaged PDAC cultures in vitro Drugs interfering with protein turnover and transcription were among most cytotoxic. Among transcriptional repressors, triptolide, a covalent inhibitor of ERCC3, was most consistently effective in vitro and in vivo causing prolonged complete regression in multiple PDX models resistant to standard PDAC therapies. Importantly, triptolide showed superior activity in MYC-amplified PDX models and elicited rapid and profound depletion of the oncoprotein MYC, a transcriptional regulator. Expression of ERCC3 and MYC was interdependent in PDACs, and acquired resistance to triptolide depended on elevated ERCC3 and MYC expression. The Cancer Genome Atlas analysis indicates ERCC3 expression predicts poor prognosis, particularly in CDKN2A-null, highly proliferative tumors., Conclusions: This provides initial preclinical evidence for an essential role of MYC-ERCC3 interactions in PDAC, and suggests a new mechanistic approach for disruption of critical survival signaling in MYC-dependent cancers. Clin Cancer Res; 22(24); 6153-63. ©2016 AACR., Competing Interests: The authors disclose no potential conflicts of interest., (©2016 American Association for Cancer Research.)

Meiosis-activating sterols (MAS) are substrates of SC4MOL and NSDHL in the cholesterol pathway and are important for normal organismal development. Oncogenic transformation by epidermal growth factor receptor (EGFR) or RAS increases the demand for cholesterol, suggesting a possibility for metabolic interference. To test this idea in vivo, we ablated Nsdhl in adult keratinocytes expressing KRAS(G12D). Strikingly, Nsdhl inactivation antagonized the growth of skin tumors while having little effect on normal skin. Loss of Nsdhl induced the expression of ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, reduced the expression of low-density lipoprotein receptor (LDLR), decreased intracellular cholesterol, and was dependent on the liver X receptor (LXR) α. Importantly, EGFR signaling opposed LXRα effects on cholesterol homeostasis, whereas an EGFR inhibitor synergized with LXRα agonists in killing cancer cells. Inhibition of SC4MOL or NSDHL, or activation of LXRα by sterol metabolites, can be an effective strategy against carcinomas with activated EGFR-KRAS signaling., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Persistent signaling by the oncogenic EGF receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase-like) and its partner, NSDHL (NADP-dependent steroid dehydrogenase-like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa(1H/+) mice confirmed dramatic and selective loss of internalized platelet-derived growth factor receptor in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL., Significance: This work identifies a critical role for SC4MOL and NSDHL in the regulation of EGFR signaling and endocytic trafficking and suggests novel strategies to increase the potency of EGFR antagonists in tumors.