Niraparib plus abiraterone acetate with prednisone in patients with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations: second interim analysis of the randomized phase III MAGNITUDE trial.

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.

Genome-wide association study of emotional empathy in children.

The genetic contribution to different aspects of empathy is now established, although the exact loci are unknown. We undertook a genome-wide association study of emotional empathy (EE) as measured by emotion recognition skills in 4,780 8-year old children from the ALSPAC cohort who were genotyped and imputed to Phase 1 version 3 of the 1000 Genomes Project. We failed to find any genome-wide significant signal in either our unstratified analysis or analysis stratified according to sex. A gene-based association analysis similarly failed to find any significant loci. In contrast, our transcriptome-wide association study (TWAS) with a whole blood reference panel identified two significant loci in the unstratified analysis, residualised for the effects of age, sex and IQ. One signal was for CD93 on chromosome 20; this gene is not strongly expressed in the brain, however. The other signal was for AL118508, a non-protein coding pseudogene, which completely lies within CD93's genomic coordinates, thereby explaining its signal. Neither are obvious candidates for involvement in the brain processes that underlie emotion recognition and its developmental pathways.

Radiographic and arthroscopic features of third carpal bone slab fractures and their impact on racing performance following arthroscopic repair in a population of racing Thoroughbreds in the UK.

BACKGROUND: Slab fractures of the third carpal bone (C3) are a common injury of Thoroughbred racehorses. Results of arthroscopically guided repair have not been reported since the initial description of the technique in 1986. Additionally, fracture details and racing outcomes in a population of Thoroughbreds racing under UK jurisdiction have not previously been described. OBJECTIVES: To report the frequency distribution of C3 slab fractures and to determine the impact on racing performance following arthroscopically guided repair in a population of Thoroughbred racehorses. STUDY DESIGN: Retrospective case series. METHODS: Case records of Thoroughbred racehorses undergoing arthroscopically guided repair of C3 slab fractures at Newmarket Equine Hospital between 2006 and 2015 were retrieved. Radiographs and arthroscopic studies were reviewed. The effect of demography and fracture morphology on racing outcome was evaluated. RESULTS: C3 slab fractures occurred most commonly through the radial facet in a frontal plane (45/71 63.4%). Comminution was identified during arthroscopy in 42/71 (59.2%) fractures and occurred most frequently at the palmar margin of the fracture. Forty-one out of 65 horses (63.1%) raced at least once post-operatively. Females were less likely to return to racing compared to males (P<0.001). Horses that had raced before injury were more likely (OR 4.4, 95% CI 1.4-13.5, P = 0.01) to race after injury compared to horses that were unraced at the time of injury. After injury horses had a small but significant reduction in racing performance. MAIN LIMITATIONS: The series is a preselected population of Thoroughbred racehorses which referring veterinary surgeons considered potential candidates for surgical repair. CONCLUSION: Fracture configurations can be identified radiographically but is not a reliable predictor of comminution or other intra-articular lesions. Arthroscopy not only directs repair but also identifies and facilitates management of concurrent lesions. The results reported should assist in formulating appropriate prognoses for Thoroughbred horses racing in the UK.

Bacterial community structure and response to nitrogen amendments in Lake Shenandoah (VA, USA).

Microbial processes are critical to the function of freshwater ecosystems, yet we still do not fully understand the factors that shape freshwater microbial communities. Furthermore, freshwater ecosystems are particularly susceptible to effects of environmental change, including influx of exogenous nutrients such as nitrogen and phosphorus. To evaluate the impact of nitrogen loading on the microbial community structure of shallow freshwater lakes, water samples collected from Lake Shenandoah (Virginia, USA) were incubated with two concentrations of either ammonium, nitrate, or urea as a nitrogen source. The potential impact of these nitrogen compounds on the bacterial community structure was assessed via 16S rRNA amplicon sequencing. At the phylum level, the dominant taxa in Lake Shenandoah were comprised of Actinobacteria and Proteobacteria, which were not affected by exposure to the various nitrogen treatments. Overall, there was not a significant shift in the diversity of the bacterial community of Lake Shenandoah with the addition of nitrogen sources, indicating this shallow system may be constrained by other environmental factors.

Apalutamide and overall survival in non-metastatic castration-resistant prostate cancer.

BACKGROUND: In the SPARTAN study, compared with placebo, apalutamide added to ongoing androgen deprivation therapy significantly prolonged metastasis-free survival (MFS) and time to symptomatic progression in patients with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC). Overall survival (OS) results at the first interim analysis (IA1) were immature, with 104 of 427 (24%) events required for planned final OS analysis. Here, we report the results of a second pre-specified interim analysis (IA2). METHODS: One thousand two hundred and seven patients with nmCRPC were randomized 2 : 1 to apalutamide (240 mg daily) or placebo. The primary end point of the study was MFS. Subsequent therapy for metastatic CRPC was permitted. When the primary end point was met, the study was unblinded. Patients receiving placebo who had not yet developed metastases were offered open-label apalutamide. At IA2, pre-specified analysis of OS was undertaken, using a group-sequential testing procedure with O'Brien-Fleming-type alpha spending function. Safety and second progression-free survival (PFS2) were assessed. RESULTS: Median follow-up was 41 months. With 285 (67% of required) OS events, apalutamide was associated with an improved OS compared with placebo (HR 0.75; 95% CI 0.59-0.96; P = 0.0197), although the P-value did not cross the pre-specified O'Brien-Fleming boundary of 0.0121. Apalutamide improved PFS2 (HR 0.55; 95% CI 0.45-0.68). At IA2, 69% of placebo-treated and 40% of apalutamide-treated patients had received subsequent life-prolonging therapy for metastatic CRPC. No new safety signals were observed. CONCLUSION: In patients with nmCRPC, apalutamide was associated with a 25% reduction in risk of death compared with placebo. This OS benefit was observed despite crossover of placebo-treated patients and higher rates of subsequent life-prolonging therapy for the placebo group.

The use of the Körperkoordinationstest für Kinder in the talent pathway in youth athletes: A systematic review.

OBJECTIVES: Identifying talented athletes from an early age to accelerate their development requires the investment of substantial resources. Due to the need for multifactorial approaches to talent identification, motor competence assessments are increasingly prevalent in contemporary testing batteries. Therefore, the aim of this review was to evaluate the literature on the use of a product-oriented motor competence assessment tool, the Körperkoordinationstest für Kinder (KTK) in the talent pathway and determine whether it is warranted in such programs. METHODS: Three electronic databases (i.e. PubMed, SPORTDiscus and Web of Science) were searched for studies that used at least one component of the KTK to assess motor competence for talent detection, identification, development and selection in athletic populations. A total of 21 articles were included in the review, of which seven used the full version of the KTK and 14 used modified versions or individual components of the battery. The quality of included studies was assessed using a modified version of the Joanna Brigg's Institute Critical Appraisal Checklist. RESULTS: The analysed literature suggests that the KTK can successfully distinguish between athletes of different competition levels and across different sporting domains, however, findings should be interpreted with caution due to the cross-sectional nature of the studies. Furthermore, the moving sideways subtest displayed the greatest discriminative power for athletes of different competition levels. Motor competence was not affected by maturation and did not differ between genders or playing positions. CONCLUSIONS: Collectively, these findings suggest that the KTK is a useful motor competence assessment in the talent pathway.

Global Health Implications of Nutrient Changes in Rice Under High Atmospheric Carbon Dioxide.

A growing literature has documented that rising concentrations of carbon dioxide in the atmosphere threaten to reduce the iron, zinc, and protein content of staple food crops including rice, wheat, barley, legumes, maize, and potatoes, potentially creating or worsening global nutritional deficiencies for over a billion people worldwide. A recent study extended these previous nutrient analyses to include B vitamins and showed that, in rice alone, the average loss of major B vitamins (thiamin, riboflavin, and folate) was shown to be 17-30% when grown under higher CO2. Here, we employ the EAR cut-point method, using estimates of national-level nutrient supplies and requirements, to estimate how B vitamin dietary adequacy may be affected by the CO2-induced loss of nutrients from rice only. Furthermore, we use the global burden of disease comparative risk assessment framework to quantify one small portion of the health burden related to rising deficiency: a higher likelihood of neural tube defects for folate-deficient mothers. We find that, as a result of this effect alone, risk of folate deficiency could rise by 1.5 percentage points (95% confidence interval: 0.6-2.6), corresponding to 132 million (57-239 million) people. Risk of thiamin deficiency could rise by 0.7 points (0.3-1.1) or 67 million people (30-110 million), and riboflavin deficiency by 0.4 points (0.2-0.6) or 40 million people (22-59 million). Because elevated CO2 concentrations are likely to reduce B vitamins in other crops beyond rice, our findings likely represent an underestimate of the impact of anthropogenic CO2 emissions on sufficiency of B vitamin intake.

Analysis of Radionuclide Deposition Ratios from the Fukushima-Daiichi Incident.

This paper will examine deposition patterns of four radionuclides following the Fukushima-Daiichi accident. For nearly 13 d following the event, fission products were released into the environment through planned venting procedures and hydrogen explosions. To assist the government of Japan (GOJ) in the assessment of the releases, the National Nuclear Security Administration's Consequence Management Response Team (CMRT) deployed and took nearly 3 mo of measurements using airborne radiation sensors, fixed monitors, high purity germanium (HPGe) detectors, and health physics survey equipment. From the HPGe detector in-situ results gathered by the CMRT and GOJ teams, the depositions of Cs, Cs, Cs, and I were examined as a function of latitude and longitude. Deposition ratios were calculated to express how each radionuclide was deposited relative to Cs. In addition, the first 30 d of results were compared to the isotopic ratios listed in the Federal Radiological Monitoring and Assessment Center (FRMAC) Dose Assessment Manual Volume 2 Nuclear Power Plant default scenario. This was completed to analyze how the default FRMAC values compared with actual measurements. For Cs:Cs and Cs:Cs (1 wk after shutdown), the ratios were 0.969 ± 0.025 and 0.13 ± 0.007, respectively. These were significantly different from the FRMAC default values of 1.6 and 0.4, but they were of the same order of magnitude. Spatially, larger ratios with high uncertainties were recorded near Tokyo, over 200 km from the accident site. The I to Cs ratios, as expected, decayed exponentially over time but were significantly higher than FRMAC values. Six ratios were greater than 20 within 10 d after shutdown compared to the FRMAC default value of 9.9. In addition, the highest ratios were located less than 75 km to the southwest of the plant. Comparing all the isotopic ratios to the FRMAC manual illustrated differences between the default values and the actual field results. This is at least partly due to the fact that the FRMAC default values are based on an average between a pressurized water reactor and boiling water reactor release. These results of the comparison illustrate that the Assessment Manual default values should only be used when no other data are available.

Frequency distribution of osteochondral fragmentation of the dorsoproximal articular surface of the proximal phalanx in racing Thoroughbreds in the UK.

BACKGROUND: Osteochondral fragmentation of the dorsoproximal margin of the proximal phalanx is commonly recognised in racing Thoroughbreds. Frequency distribution has been documented in racing Thoroughbreds and Quarter Horses in the USA and in European Warmbloods but no data have been published from the UK. Concurrent intra-articular soft tissue lesions and radiographic accuracy of fragment distribution in racing Thoroughbreds have not previously been reported. OBJECTIVES: To document frequency distribution of dorsoproximal fragmentation of the proximal phalanx in a UK population of racing Thoroughbreds and to compare this with published data. To document concurrent intra-articular lesions identified arthroscopically and radiographic accuracy of fragment distribution. STUDY DESIGN: A retrospective single centre-based, observational study. METHODS: Surgical reports and radiographs of all racing Thoroughbreds that underwent arthroscopic surgery for removal of fragmentation from the dorsoproximal margin of the proximal phalanx at Newmarket Equine Hospital between 2011 and 2015 were reviewed. RESULTS: Two hundred and forty-two (85.8%) horses were in or being prepared for flat racing. Osteochondral fragmentation of the dorsoproximal aspect of the proximal phalanx was present in 428 fetlock joints of 282 horses, consisting of 194 (45.3%) left and 188 (43.9%) right metacarpophalangeal joints, and 20 (4.7%) left and 26 (6.1%) right metatarsophalangeal joints. Fragmentation was located dorsomedially in 316 (73.8%), dorsolaterally in 32 (7.5%) and biaxially in 80 (18.7%) joints. Concurrent soft tissue lesions were identified in 168 (39.3%) joints. Radiographic evidence of fragmentation was visible in 320 joints (74.8%). MAIN LIMITATIONS: Limited numbers preclude conclusions with respect to yearlings and horses in jump race training. CONCLUSION: Dorsoproximal fragmentation of the proximal phalanx occurred most frequently medially and in the forelimbs. Sidedness was not demonstrated. Although similar to previously reported data, variance in limb distribution is evident. Further research is required to determine whether concurrent intra-articular soft tissue lesions are aetiopathogenic or an additional result of the pathological changes leading to fragmentation. Fragmentation site was not always accurately identified radiographically. The Summary is available in Spanish - see Supporting information.

Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.

BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.

Parasagittal fractures of the proximal phalanx in Thoroughbred racehorses in the UK: Outcome of repaired fractures in 113 cases (2007-2011).

BACKGROUND: Thirty years have elapsed since the last published review of outcome following fracture of the proximal phalanx in Thoroughbred racehorses in the UK and contemporary results are needed to be able to advise of expected outcome. OBJECTIVES: Collect and analyse outcome data following repair of fractures of the proximal phalanx in Thoroughbred racehorses in the UK. STUDY DESIGN: Retrospective case series. METHODS: Case records of all Thoroughbred racehorses admitted to Newmarket Equine Hospital for evaluation of a parasagittal fracture of the proximal phalanx during a 5 years period were reviewed. Follow-up data regarding racing careers was collected for horses that underwent repair. Following exclusion of outliers, cases with incomplete data sets and comminuted fractures, mixed effect logistic regression was used to identify variables affecting returning to racing and odds ratios and confidence intervals calculated. RESULTS: Of 113 repaired cases, fracture configurations included short incomplete parasagittal (n = 12), long incomplete parasagittal (n = 86), complete parasagittal (n = 12) and comminuted (n = 3). A total of 54 (48%) cases raced after surgery. Horses that fractured at 2 years of age had increased odds of racing following surgery than those older than 2 years of age (OR 1.34; 95% CI 1.13-1.59, P = 0.002). Horses sustaining short incomplete parasagittal fractures had increased odds of racing following surgery compared with those with complete parasagittal fractures (OR 2.62; 95% CI 1.36-5.07, P = 0.006). No horses with comminuted fractures returned to racing. MAIN LIMITATIONS: Data are relevant only to Thoroughbred racehorses in the UK. CONCLUSIONS: Approximately half of the cases in this series raced following surgical repair. More 2-year-old horses raced following surgery, but this likely reflects horses, specifically older horses, passing out of training from unrelated factors. Fracture configuration affects odds of racing, which is relevant to owners when deciding on treatment.

Potential rise in iron deficiency due to future anthropogenic carbon dioxide emissions.

Iron deficiency reduces capacity for physical activity, lowers IQ, and increases maternal and child mortality, impacting roughly a billion people worldwide. Recent studies have shown that certain highly consumed crops-C3 grains (e.g., wheat, rice, and barley), legumes, and maize-have lower iron concentrations of 4-10% when grown under increased atmospheric CO2 concentrations (550 ppm). We examined diets in 152 countries globally (95.5% of the population) to estimate the percentage of lost dietary iron resulting from anthropogenic CO2 emissions between now and 2050, specifically among vulnerable age-sex groups: children (1-5 years) and women of childbearing age (15-49 years), holding diets constant. We also cross-referenced these with the current prevalence of anemia to identify most at-risk countries. We found that 1.4 billion children aged 1-5 and women of childbearing age (59% of global total for these groups) live in high-risk countries, where the prevalence of anemia exceeds 20% and modeled loss in dietary iron would be in the most severe tertile (>3.8%). The countries with the highest anemia prevalence also derive their iron from the fewest number of foods, even after excluding countries consuming large amounts of unaccounted wild-harvest foods. The potential risk of increased iron deficiency adds greater incentive for mitigating anthropogenic CO2 emissions and highlights the need to address anticipated health impacts via improved health delivery systems, dietary behavioral changes, or agricultural innovation. Because these are effects on content rather than yield, it is unlikely that consumers will perceive this health threat and adapt to it without education.

Effect of denosumab versus zoledronic acid in preventing skeletal-related events in patients with bone metastases by baseline characteristics.

BACKGROUND: Analyses of phase III trials showed that denosumab was superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) irrespective of age, history of SREs, or baseline pain status. This analysis assessed the risk of SREs across additional baseline characteristics. PATIENTS AND METHODS: Patients (N = 5543) from three phase III trials who had breast cancer, prostate cancer, or other solid tumours and one or more bone metastasis were included. Superiority of denosumab versus ZA in reducing risk of first SRE and first and subsequent SREs was assessed in subgroups defined by the Eastern Cooperative Oncology Group performance status (ECOG PS), bone metastasis location, bone metastasis number, visceral metastasis presence/absence, and urinary N-telopeptide (uNTx) level using Cox proportional hazards and Anderson-Gill models. Subgroups except bone metastasis location were also assessed for each solid tumour type. RESULTS: Compared with ZA, denosumab significantly reduced the risk of first SRE across all subgroups (hazard ratio [HR] ranges: ECOG PS, 0.79-0.84; bone metastasis location, 0.78-0.83; bone metastasis number, 0.78-0.84; visceral metastasis presence/absence, 0.80-0.82; uNTx level, 0.73-0.86) and reduced the risk of first and subsequent SREs in all subgroups (HR ranges: ECOG PS, 0.76-0.83; bone metastasis location, 0.78-0.84; bone metastasis number, 0.79-0.81; visceral metastasis presence/absence, 0.79-0.81; uNTx level, 0.74-0.83). Similar results were observed in subgroups across tumour types. CONCLUSION: Denosumab was superior to ZA in preventing SREs in patients with bone metastases from advanced cancer, regardless of ECOG PS, bone metastasis number, baseline visceral metastasis presence/absence, and uNTx level.

Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015.

The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naïve prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged.

Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a hematological cancer associated with an aggressive clinical course. The predominant subtypes of DLBCL display features of chronic or tonic B-cell antigen receptor (BCR) signaling. However, it is not known whether the spatial organization of the BCR contributes to the regulation of pro-survival signaling pathways and cell growth. Here, we show that primary DLBCL tumors and patient-derived DLBCL cell lines contain high levels of phosphorylated Ezrin-Radixin-Moesin (ERM) proteins. The surface BCRs in both activated B cell and germinal B cell subtype DLBCL cells co-segregate with phosphoERM suggesting that the cytoskeletal network may support localized BCR signaling and contribute to pathogenesis. Indeed, ablation of membrane-cytoskeletal linkages by dominant-negative mutants, pharmacological inhibition and knockdown of ERM proteins disrupted cell surface BCR organization, inhibited proximal and distal BCR signaling, and reduced the growth of DLBCL cell lines. In vivo administration of the ezrin inhibitor retarded the growth of DLBCL tumor xenografts, concomitant with reduction in intratumor phosphoERM levels, dampened pro-survival signaling and induction of apoptosis. Our results reveal a novel ERM-based spatial mechanism that is coopted by DLBCL cells to sustain tumor cell growth and survival.

MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies.

Overexpression of anti-apoptotic BCL-2 family members is a hallmark of many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 is a rationally designed BCL-2 homology (BH)-3 mimetic that specifically binds to BCL-2, but not to MCL-1 and BCL-xL. Although the thrombocytopenia that occurs with navitoclax treatment has not been a problem with ABT-199, clinical trials in CLL could benefit by lowering the ABT-199 concentration through targeting other survival pathways. In this study, we investigated the mechanisms of resistance that develops to ABT-199 therapy by generating ABT-199-resistant (ABT199-R) cell lines via chronic exposure of NHL cell lines to ABT-199. Acquired resistance resulted in substantial AKT activation and upregulation of MCL-1 and BCL-xL levels that sequestered BIM. ABT199-R cells exhibited increased MCL-1 stability and failed to activate BAX in response to ABT-199. The ABT-199 acquired and inherent resistant cells were sensitized to treatment with ABT-199 by inhibitors of the PI3K, AKT, and mTOR pathways, NVP-BEZ235 and GS-1101. NVP-BEZ235, a dual inhibitor of p-AKT and mTOR, reduced MCL-1 levels causing BIM release from MCL-1 and BCL-xL, thus leading to cell death by BAX activation. The PI3Kδ inhibitor GS-1101 (idelalisib) downregulated MCL-1 and sensitized ABT199-R cells through AKT-mediated BAX activation. A genetic approach, through siRNA-mediated down-regulation of AKT, MCL-1, and BCL-xL, significantly decreased cell survival, demonstrating the importance of these cell survival factors for ABT-199 resistance. Our findings suggest a novel mechanism that modulates the expression and activity of pro-survival proteins to confer treatment resistance that could be exploited by a rational combination therapeutic regimen that could be effective for treating lymphoid malignancies.