Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence.

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression. Critically, MYC activation was necessary and sufficient for resistance, and suppression of MYC activity using genetic approaches or BET bromodomain inhibition was sufficient to resensitize cells and delay BRAFi resistance. Finally, MYC-driven, BRAFi-resistant cells are hypersensitive to the inhibition of MYC synthetic lethal partners, including SRC family and c-KIT tyrosine kinases, as well as glucose, glutamine, and serine metabolic pathways. These insights enable the design of combination therapies that select against resistance evolution.

The Epidemic of Despair Among White Americans: Trends in the Leading Causes of Premature Death, 1999-2015.

OBJECTIVES: To evaluate trends in premature death rates by cause of death, age, race, and urbanization level in the United States. METHODS: We calculated cause-specific death rates using the Compressed Mortality File, National Center for Health Statistics data for adults aged 25 to 64 years in 2 time periods: 1999 to 2001 and 2013 to 2015. We defined 48 subpopulations by 10-year age groups, race/ethnicity, and county urbanization level (large urban, suburban, small or medium metropolitan, and rural). RESULTS: The age-adjusted premature death rates for all adults declined by 8% between 1999 to 2001 and 2013 to 2015, with decreases in 39 of the 48 subpopulations. Most decreases in death rates were attributable to HIV, cardiovascular disease, and cancer. All 9 subpopulations with increased death rates were non-Hispanic Whites, largely outside large urban areas. Most increases in death rates were attributable to suicide, poisoning, and liver disease. CONCLUSIONS: The unfavorable recent trends in premature death rate among non-Hispanic Whites outside large urban areas were primarily caused by self-destructive health behaviors likely related to underlying social and economic factors in these communities.

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.

PIK3CA mutations enable targeting of a breast tumor dependency through mTOR-mediated MCL-1 translation.

Therapies that efficiently induce apoptosis are likely to be required for durable clinical responses in patients with solid tumors. Using a pharmacological screening approach, we discovered that combined inhibition of B cell lymphoma-extra large (BCL-XL) and the mammalian target of rapamycin (mTOR)/4E-BP axis results in selective and synergistic induction of apoptosis in cellular and animal models of PIK3CA mutant breast cancers, including triple-negative tumors. Mechanistically, inhibition of mTOR/4E-BP suppresses myeloid cell leukemia-1 (MCL-1) protein translation only in PIK3CA mutant tumors, creating a synthetic dependence on BCL-XL This dual dependence on BCL-XL and MCL-1, but not on BCL-2, appears to be a fundamental property of diverse breast cancer cell lines, xenografts, and patient-derived tumors that is independent of the molecular subtype or PIK3CA mutational status. Furthermore, this dependence distinguishes breast cancers from normal breast epithelial cells, which are neither primed for apoptosis nor dependent on BCL-XL/MCL-1, suggesting a potential therapeutic window. By tilting the balance of pro- to antiapoptotic signals in the mitochondria, dual inhibition of MCL-1 and BCL-XL also sensitizes breast cancer cells to standard-of-care cytotoxic and targeted chemotherapies. Together, these results suggest that patients with PIK3CA mutant breast cancers may benefit from combined treatment with inhibitors of BCL-XL and the mTOR/4E-BP axis, whereas alternative methods of inhibiting MCL-1 and BCL-XL may be effective in tumors lacking PIK3CA mutations.

Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.

Genomes on the edge: programmed genome instability in ciliates.

Ciliates are an ancient and diverse group of microbial eukaryotes that have emerged as powerful models for RNA-mediated epigenetic inheritance. They possess extensive sets of both tiny and long noncoding RNAs that, together with a suite of proteins that includes transposases, orchestrate a broad cascade of genome rearrangements during somatic nuclear development. This Review emphasizes three important themes: the remarkable role of RNA in shaping genome structure, recent discoveries that unify many deeply diverged ciliate genetic systems, and a surprising evolutionary "sign change" in the role of small RNAs between major species groups.

Serum 25-hydroxyvitamin D concentrations in girls aged 4-8 y living in the southeastern United States.

BACKGROUND: Evidence suggests that adults and adolescents throughout the United States are at risk of poor vitamin D status. However, vitamin D concentrations in young American children have not been assessed. OBJECTIVE: The relations between serum 25-hydroxyvitamin D [25(OH)D] and bone were examined in prepubertal girls. DESIGN: In the present cross-sectional study, serum 25(OH)D concentration was assessed in 168 prepubertal girls aged 4-8 y living in the southeastern United States with the use of radioimmunoassay. Bone area, bone mineral content, and areal bone mineral density were measured from total body, lumbar spine, proximal femur, and forearm with dual-energy X-ray absorptiometry. Data were analyzed with analysis of variance, analysis of covariance, stepwise multiple regression, and partial correlations. RESULTS: The mean (+/-SD) serum 25(OH)D was 93.8 +/- 28.1 nmol/L (range: 31.1-181.4 nmol/L). In a multiple regression analysis, race and season were the strongest predictors of vitamin D status. The black girls had lower mean 25(OH)D values than did the white girls (P < 0.01), and 25(OH)D values were significantly different in the total sample between the seasons (P < 0.001), ranging from 74.4 nmol/L during the winter months to 107 nmol/L during the summer. After adjustment for season, age, race, and body mass index, 25(OH)D values were negatively correlated with forearm bone mineral content (r = -0.18; P = 0.02). CONCLUSIONS: Unlike prior reports of adults and adolescents living in the southeastern United States, vitamin D status was adequate in the children of the present study. 25(OH)D concentrations were not positively associated with higher bone mineral.