Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas.

KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

Heterogeneous Off-Target Effects of Ultra-Low Dose Dimethyl Sulfoxide (DMSO) on Targetable Signaling Events in Lung Cancer In Vitro Models.

Targetable alterations in cancer offer novel opportunities to the drug discovery process. However, pre-clinical testing often requires solubilization of these drugs in cosolvents like dimethyl sulfoxide (DMSO). Using a panel of cell lines commonly used for in vitro drug screening and pre-clinical testing, we explored the DMSO off-target effects on functional signaling networks, drug targets, and downstream substrates. Eight Non-Small Cell Lung Cancer (NSCLC) cell lines were incubated with three concentrations of DMSO (0.0008%, 0.002%, and 0.004% v/v) over time. Expression and activation levels of 187 proteins, of which 137 were kinases and downstream substrates, were captured using the Reverse Phase Protein Array (RPPA). The DMSO effect was heterogeneous across cell lines and varied based on concentration, exposure time, and cell line. Of the 187 proteins measured, all were statistically different in at least one comparison at the highest DMSO concentration, followed by 99.5% and 98.9% at lower concentrations. Only 46% of the proteins were found to be statistically different in more than 5 cell lines, indicating heterogeneous response across models. These cell line specific alterations modulate response to in vitro drug screening. Ultra-low DMSO concentrations have broad and heterogeneous effects on targetable signaling proteins. Off-target effects need to be carefully evaluated in pre-clinical drug screening and testing.

Prevalence and Factor Structure of PTSD in DSM-5 Versus DSM-IV in a National Sample of Sexual Minority Women.

The impact of changes to posttraumatic stress disorder (PTSD) diagnostic criteria from Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) to Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) within diverse communities is unclear. Young adult sexual minority women are at high risk for interpersonal violence and other forms of trauma exposure compared with heterosexual populations and sexual minority men. They are also at heightened risk of PTSD. As a result, young adult sexual minority women are a key population of interest when examining the impact of diagnostic criteria changes. The goal of the current study was to evaluate the impact of changes to PTSD diagnostic criteria in sexual minority women. Using an online survey, we administered both the original PTSD Symptom Checklist-S (based on DSM-IV criteria) and a version adapted to assess DSM-5 criteria to a national, nonclinical sample of young adult sexual minority women (N = 767). The DSM-5 symptom criteria fit the data well in confirmatory factor analysis. Current PTSD prevalence was higher under the DSM-5 diagnostic algorithm compared with DSM-IV (18.6% vs. 22.9%; d = 0.15). Compared with DSM-IV, associations between PTSD and depression were stronger using DSM-5 criteria, whereas associations between PTSD and high-risk drinking were reduced. Findings suggest that changes to PTSD diagnostic criteria do not have a major impact on prevalence of PTSD among sexual minority women but may have some impact on observed comorbidities.

Changes in Sexual Identity and Associations With Alcohol Use and Depression Among Young Adult Sexual Minority Women.

OBJECTIVE: Sexual minority women report more problematic alcohol use and depression than heterosexual women. Despite evidence that sexual identity can change over time, most studies treat it as a static construct. As a result, little is known about the extent to which changes in sexual identity influence alcohol use and depression. The current study examined (a) changes in sexual identity over 36 months, (b) the associations between the number of changes in sexual identity and measures of alcohol use (typical weekly alcohol consumption, peak drinking, and alcohol-related consequences) and depression at the final assessment, and (c) baseline sexual identity as a moderator of the associations. METHOD: The analyses used four waves of data from a national U.S. sample of sexual minority women ages 18-25 (n = 1,057). RESULTS: One third (34%) of participants reported at least one change in sexual identity over the course of the study. The number of changes in sexual identity was positively associated with typical weekly alcohol consumption and depression but was not significantly associated with peak drinking or alcohol-related consequences. None of the associations were moderated by baseline sexual identity. CONCLUSIONS: These findings provide additional evidence that sexual identity continues to change over time for a sizeable proportion of young adult sexual minority women and these changes are relevant to their health and well-being.

Alcohol and binge eating as mediators between posttraumatic stress disorder symptom severity and body mass index.

OBJECTIVE: Sexual-minority women are at elevated risk for obesity, as well as exposure to traumatic events. Rates of obesity are elevated in individuals with posttraumatic stress disorder (PTSD), but little is known about why this relationship exists. Behavioral mechanisms, such as eating patterns and alcohol use, are possible explanations that would be clinically useful to identify. METHODS: Binge eating and alcohol use were longitudinally investigated as mediators of the relationship between PTSD symptom severity and body mass index (BMI) in a large sample of young-adult, sexual-minority women (N = 425). PTSD symptom severity was assessed at baseline, binge eating and alcohol use were assessed 12 months later, and BMI was assessed 24 months after baseline. RESULTS: Using a multiple mediator model, higher baseline PTSD symptom severity was found to be significantly associated with higher BMI 2 years later, operating through binge-eating behavior but not through alcohol use. Exploratory moderator analyses found that this effect was higher for those with lower baseline BMI. CONCLUSIONS: Results suggest that higher PTSD symptoms are longitudinally associated with increased BMI and that binge eating behavior is one factor that explains this relationship.

Minority stress is longitudinally associated with alcohol-related problems among sexual minority women.

Compared to sexual minority men and heterosexual women, sexual minority women report elevated alcohol use in young adulthood. Heavy alcohol use and alcohol use disorders disproportionately affect sexual minority women across the lifespan, yet there is limited research investigating reasons for such associations. The present study investigates longitudinal associations between minority stress and both alcohol use as well as self-rated drinking consequences. Participants (N=1057) were self-identified lesbian (40.5%) and bisexual (59.5%) women between the ages of 18 to 25 recruited from across the U.S. using online advertisements. Participants completed four annual surveys. Hurdle mixed effects models were used to assess associations between minority stress and typical weekly drinking and drinking consequences one year later. Minority stress was not significantly associated with subsequent typical drinking. However, minority stress was significantly associated with having any alcohol consequences as well as the count of alcohol consequences one year later after controlling for covariates. Consistent with extant literature, this study provides evidence for a prospective association between minority stress experienced by sexual minority women and drinking consequences. This study also provides support for the potential impact of efforts to reduce minority stress faced by sexual minority women.

Reciprocal relationships over time between descriptive norms and alcohol use in young adult sexual minority women.

Young adulthood, roughly ages 18-25, is a period of great risk for excessive consumption of alcohol, especially among sexual minority women (SMW). Despite the substantial literature examining the relationships between social norms and behavior in general, little attention has been given to the role of descriptive norms on the drinking behaviors of sexual minorities. The present study had 3 aims: to compare both typical woman descriptive norms and sexual minority-specific descriptive normative perceptions among a sample of SMW, to examine reciprocal associations between sexual minority-specific descriptive norms and alcohol consumption over time, and to examine whether these reciprocal associations were moderated by sexual orientation (i.e., whether 1 identifies as lesbian or bisexual). A national sample of 1,057 lesbian and bisexual women between the ages of 18 and 25 was enrolled in this study. Participants completed an online survey at 4 time points that assessed the constructs of interest. Results indicated that SMW consistently perceived that SMW drank more than their nonsexual minority peers; that SMW-specific descriptive drinking norms and alcohol consumption influenced 1 another over time in a reciprocal, feed-forward fashion; and that these associations were not moderated by sexual orientation. These findings highlight the importance of considering SMW-specific norms as an important factor in predicting alcohol consumption in SMW. Results further support the development and testing of normative interventions for high-risk drinking among SMW.