bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA7: Novel mechanisms of resistance in BRAF-mutant melanoma
Authors: Poulikakos Poulikos I. 
Published: March 2013

Abstract
Tumors with mutant BRAF(V600E) are dependent on ERK signaling for their growth. Unlike MEK inhibitors that suppress ERK signaling in all cells, RAF inhibitors suppress ERK signaling in cells with mutant BRAF, but paradoxically enhance ERK signaling in tumor and normal cells with wild-type BRAF. The mechanistic basis of this phenomenon lies in the interaction of these drugs with RAF dimers. Active RAS promotes homo- and heterodimerization of RAF. Binding of drug to one protomer in the RAF dimer transactivates the other. In BRAF(V600E) tumors, RAS is not activated, RAF is a monomer and thus transactivation is minimal. In these tumors, RAF inhibitors bind to and inhibit the RAF monomer and effectively suppress ERK signaling. Furthermore, because RAF inhibitors do not inhibit ERK signaling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumor activity than MEK inhibitors. Indeed, RAF inhibitors have shown remarkable clinical activity in patients with melanomas that harbor mutant BRAF(V600E), however, resistance invariably develops. The mechanism of action of these drugs suggests that drug resistance could result from any lesion that increases RAF dimerization. These could include mechanisms that increase RAS activation in the tumor cells or lesions that cause RAF to dimerize in a RAF-independent manner. Indeed, mutations in NRAS and activation of receptor tyrosine kinases have now been associated with innate or acquired resistance to RAF inhibitors. We have found that aberrantly spliced forms of BRAF(V600E) are associated with resistance to RAF inhibitors in preclinical models and in patients that relapsed on the RAF inhibitor vemurafenib (PLX4032). These variants lack the RAS-binding domain, constitutively homodimerize in cells with low levels of RAS activity and confer resistance to the drug. Thus, RAF dimerization emerges as a common theme in RAF-inhibitor resistance mechanisms. Since a large part of resistance to RAF inhibitors is attributable to attenuation of the ability of the drug to inhibit RAF, one would predict that such tumors would retain at least partial sensitivity to inhibitors of downstream effectors of RAF such as MEK or ERK. Therefore, combinatorial approaches targeting upstream or downstream of RAF in addition to RAF inhibitors may delay or prevent the onset of these mechanisms of resistance.
Abstract IA9: The MEK network as a target for combination therapies
Authors: Korn W. Michael 
Published: March 2013

Abstract
Small molecule inhibitors of signal transduction pathways can elicit complex and sometimes non-intuitive molecular responses in cancer cells. Increasing evidence supports the notion that these responses are important mediators of de novo drug resistance. We systematically assessed molecular and cellular responses to MEK inhibitors, aiming at identifying meaningful targets for combination therapies. Proteomic analyses revealed an EGFR-dependent feedback loop resulting in activation of the PI3 kinase pathway following MEK inhibition. In agreement with this, combinations of MEK inhibitors and inhibitors of EGFR inhibitors or PI3 kinase show synergistic effects on cell proliferation and apoptosis rates in molecularly defined disease subtypes. To further explore molecular networks affected by MEK inhibition, Bayesian network inference algorithms were applied and reverse-engineered networks were generated that are amenable to in silico forward-simulation. Using this technology, new, MEK-dependent, novel regulators of cell cycle and apoptosis were identified and experimentally validated. These findings highlight the potential of mathematical modeling approaches to efficiently reveal new and therapeutically relevant features of signal transduction networks.
Abstract PR2: Stroma-derived matrix metalloproteinase 9 (MMP9) confers resistance to anti-EGFR therapy through cell-extrinsic activation of ERBB2/ERK/JUN pathway
Authors: Woo Janghee , Teppei Morikawa , Ogino Shuji , Shivdasani Ramesh A. 
Published: March 2013

Abstract
Matrix metalloproteinases (MMPs) have been studied historically for their role in tissue invasion and metastasis. The tumor microenvironment also produces MMPs that may influence other tumor behaviors, as recent mouse models suggest in the intestine and other sites. We examined MMP9 expression in 642 cases of human colorectal cancer (CRC) in relation to clinicopathological features and mutations. MMP9 antibody (Ab) unambiguously stained mesenchymal cells in 104 cases (16.2%) and gave weaker stromal staining in another 12.8%. High stromal MMP9 expression correlated most strongly with the CpG island methylator phenotype (CIMP-high) in tumors (multivariate odds ratio – OR – 2.45, 95% confidence interval – CI – 1.41 to 4.27, p=0.0015) and also with absence of tumor KRAS mutations (multivariate OR 0.54, 95% CI 0.33 to 0.87, p=0.011). The latter association suggested KRAS allelic status as one reason for heterogeneity in CRC cell line responses to MMP9. Four out of 6 KRASWT cell lines proliferated significantly more in the presence of exogenous MMP9, while 4 of 5 KRASMut lines failed to respond. This led us to ask if stromal MMP9 expression might predict the outcome of treatment with anti-EGFR mAb cetuximab, allowing KRASWT tumors to bypass mAb blockade of EGFR-KRAS pathway activation. We retrospectively evaluated MMP9 expression by immunohistochemistry on primary tumors and progression-free survival (PFS) in 86 patients who had received chemotherapy combined with cetuximab as first-line or salvage therapy. Tumors from 29 patients (33.8%) harbored mutant KRAS. PFS of patients with MMP9high;KRASWT tumors (median 3.5 months) was lower than that of patients with low or no stromal MMP9 expression and KRASWT tumors (median 5.8 months, 95% CI for the hazard ratio 1.135-2.179). Patients with KRASMut tumors showed no significant difference in PFS with respect to MMP9 expression (2.55 months and 2.25 months in the MMP9high and MMP9neg/low subgroups, respectively). Thus, low stromal MMP9 expression in KRASWT tumors predicted a better outcome with cetuximab treatment than high MMP9 expression. In CRC cell lines that grow faster in response to MMP9, this factor activates ERBB2 and ERK/JUN signaling. Together, these findings suggest that stroma-derived MMP9 may help tumors bypass common mutational mechanisms for constitutive growth factor pathway activation and confer resistance to anti-EGFR therapy through cell-extrinsic activation of the ERBB2/ERK/JUN pathway. Stromal MMP9 expression may thus predict cetuximab response in KRASWT CRCs and have value in selecting patients for treatment.
This proffered talk is also presented as Poster A26.
Abstract PR5: Identifying mechanisms of drug resistance to MAPK pathway inhibition via genome-scale rescue screens
Authors: Johannessen Cory M. , Johnson Laura A. , Lam Daniel , Hamm Luke , Piccioni Federica , Root David , Garraway Levi 
Published: March 2013

Abstract
The recent clinical success of RAF inhibitors in BRAF(V600E)-mutant malignant melanoma highlights the promise of targeted therapeutics as well as the inevitability of acquired drug resistance: responses are sustained for less than a year and all patients ultimately become drug resistant. To identify causative drug resistance genes in BRAF(V600E)-mutant melanoma, we have individually expressed over 14, 000 unique genes and queried their ability to affect sensitivity to a panel of mitogen activated protein kinase (MAPK) pathway inhibitors, including a RAF, MEK and ERK inhibitor, both as single agents or in combination (RAFi+MEKi). Out of this genome-scale collection, less than 1% of genes are sufficient to induce resistance to the MAPK pathway inhibitors tested. Here, we present the results of this rescue screen and extensive validation/characterization efforts that reveal a number of novel insights into mechanisms of drug resistance, melanoma biology and the MAPK signaling pathway. Additionally, the scale of this first-of-kind functional rescue screen permits its integration with existing genome characterization efforts, including melanoma sequencing studies, gene expression data and parallel functional assays to identify the most relevant genetic modifiers of resistance to MAPK pathway inhibition.
This proffered talk is also presented as Poster B27.
Abstract PR6: Widespread potential for growth factor-driven resistance to anti-cancer kinase inhibitors
Authors: Wilson Timothy R. , Fridlyand Jane , Ribas Antoni , Li Jiang , Koeppen Hartmut , Merchant Mark , Neve Richard , Settleman Jeff , Yan Yibing , Penuel Elicia , Burton Luciana , Chan Emily , Peng Jing , Lin Eva , Wang Yulei , Sosman Jeff 
Published: March 2013

Abstract
Mutationally activated kinases, including EGFR, HER2, ALK, ABL, PDGFR, c-KIT, and BRAF, define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumors harbor such alleles is invariably limited by innate or acquired drug resistance. As molecular mechanisms of resistance have begun to be elucidated, a recurrent theme is the engagement of survival signals redundant to those transduced by the targeted oncogenic kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs), and many of these can potentially mediate signals that converge on common and critical downstream cell survival effectors - most notably, PI-3 kinase (PI3K) and MAP kinase (MAPK). Consequently, an increase in RTK ligand levels, via autocrine tumor cell production, paracrine contribution by tumor stroma, or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar downstream signaling output. Indeed, using a large panel of kinase-“addicted” cancer cell lines, we found that the vast majority of such cells can be “rescued” from drug sensitivity by simply exposing them to one or more RTK ligands that engage redundant survival effectors. Among the findings with immediate clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the HER2 kinase inhibitor lapatinib in HER2 amplified breast cancer cells, and to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF mutant melanoma cells. Analysis of systemic HGF levels from PLX4032-treated BRAF mutant metastatic melanoma patients who were enrolled on the BRIM2 study indicated that increased HGF levels were significantly associated with a worse clinical outcome. These observations highlight the extensive redundancy of RTK-transduced signaling in cancer cells and the potentially broad role of widely expressed RTK ligands in both innate and acquired resistance to drugs targeting oncogenic kinases.
This proffered talk is also presented as Poster B38.
Abstract PR7: Paracrine receptor activation by microenvironment triggers bypass survival signals and ALK inhibitor-resistance in EML4-ALK lung cancer cells
Authors: Yano Seiji , Takeuchi Shinji , Nakagawa Takayuki , Yamada Tadaaki 
Published: March 2013

Abstract
Cancer cell microenvironments, including host cells, can critically affect cancer cell behaviors, including drug sensitivity. We recently reported that hepatocyte growth factor (HGF), the ligand of a tyrosine kinase receptor Met, can be produced not only by cancer cells but also host fibroblasts, activates Met and the downstream PI3K/Akt pathway and triggers resistance to EGFR inhibitors in EGFR mutant lung cancer cells (Yano S et al, Cancer Res, 2008). Crizotinib, a dual inhibitor of ALK and Met, shows dramatic effects against EML4-ALK lung cancer cells, but these cells can acquire resistance by several mechanisms, including ALK amplification and gatekeeper mutation. Although elective ALK inhibitors can overcome crizotinib resistance due to these mechanisms, these cells may become resistant to these inhibitors. Here, we determined whether microenvironmental factors trigger ALK inhibitor resistance in EML4-ALK lung cancer cells.
We tested the effects of ligands produced by endothelial cells and fibroblasts, and the cells themselves, on the susceptibility of EML4-ALK lung cancer cell lines to crizotinib and TAE684, a selective ALK inhibitor active against cells with ALK amplification and gatekeeper mutations, both in vitro and in vivo. EML4-ALK lung cancer cells were highly sensitive to ALK inhibitors. EGFR ligands, such as EGF, TGF-α, and HB-EGF, activated EGFR and triggered resistance to crizotinib and TAE684 by transducing bypass survival signaling through Erk1/2 and Akt. HGF activated Met/Gab1 and triggered resistance to TAE684, but not crizotinib, which inhibits Met. Endothelial cells and fibroblasts, which produce the EGFR ligands and HGF, respectively, decreased the sensitivity of EML4-ALK lung cancer cells to crizotinib and TAE684, respectively. EGFR-TKIs re-sensitized these cells to crizotinib and Met-TKI to TAE684 even in the presence of EGFR ligands and HGF, respectively.
Our findings suggest that paracrine receptor activation by ligands from the microenvironment may trigger resistance to ALK inhibitors in EML4-ALK lung cancer cells, and provide a rationale for targeting receptor ligands in the microenvironment for more successful treatment with ALK inhibitors. These observation further raise clinical questions which classes ALK inhibitors are more beneficial for EML4-ALK lung cancer patients.
This proffered talk is also presented as Poster A30.
Abstract PR8: Insensitivity to RAF inhibition by vemurafenib in BRAF mutant colorectal cancer by EGFR-mediated reactivation of MAPK signaling
Authors: Corcoran Ryan B. , Hung Kenneth E. , Flaherty Keith T. , Piris Adriano , Wargo Jennifer A. , Settleman Jeffrey , Mino-Kenudson Mari , Engelman Jeffrey A. , Ebi Hiromichi , Turke Alexa B. , Coffee Erin M. , Nishino Michiya , Cogdill Alexandria P. , Brown Ronald D. , Pelle Patricia Della , Dias-Santagata Dora 
Published: March 2013

Abstract
BRAF mutations occur in 10–15% of colorectal cancers (CRCs) and confer adverse outcome in the metastatic setting. While RAF inhibitors such as vemurafenib (PLX4032) have proven effective in BRAF mutant melanoma (∼60–80% response rates), they are surprisingly ineffective in BRAF mutant CRCs (∼5% response rate), and the reason for this disparity remains unclear. Compared to BRAF mutant melanoma cells, BRAF mutant CRC cells were less sensitive to vemurafenib, and P-ERK suppression was not sustained in response to treatment. Although transient inhibition of phospho-ERK by vemurafenib was observed in CRC, rapid ERK re-activation occurred through EGFR-mediated activation of RAS and CRAF. BRAF mutant CRC cell lines and patient tumor specimens expressed significantly higher levels of phospho-EGFR than BRAF mutant melanoma cell lines and primary tumor specimens, suggesting that CRCs are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of MAPK signaling in BRAF mutant CRC cells and markedly improved efficacy in vitro. In vivo, combined RAF and EGFR inhibition led to sustained suppression of MAPK signaling and to robust tumor regressions in BRAF mutant colorectal xenografts. These findings support evaluation of combined RAF and EGFR inhibition in clinical trials in patients with BRAF mutant CRC.
This proffered talk is also presented as Poster B11.
Is Diabetes Mellitus a Heart Disease Equivalent in Women?
Authors: Daniels Lori B. , Grady Deborah , Mosca Lori , Collins Peter , Mitlak Bruce H. , Amewou-Atisso Messan G. , Wenger Nanette K. , Barrett-Connor Elizabeth ,   for the Raloxifene Use for the Heart (RUTH) Trial Investigators
Published: March 2013

Background—
Several studies have concluded that diabetes mellitus and heart disease carry similar risk for future cardiovascular disease (CVD). Most of these studies were too small to quantify independent risks specific to women. The purpose of this study was to determine whether diabetes mellitus is a coronary heart disease (CHD) risk equivalent for prediction of future CHD and CVD events in women.

Methods and Results—
The Raloxifene Use for the Heart (RUTH) trial was an international, multicenter, double-blind, randomized, placebo-controlled trial of raloxifene and CVD outcomes in 10 101 postmenopausal women selected for high CHD risk. Of these, 3672 had a history of diabetes mellitus without known CHD, and 3265 had a history of CHD without known diabetes mellitus. Cox proportional hazard models were used to compare cardiovascular outcomes in these 2 groups. Mean age at baseline was 67.5 years; median follow-up was 5.6 years. There were 725 deaths, including 450 cardiovascular deaths. In age-adjusted analyses, diabetic women had an increased risk of all-cause mortality compared with women with CHD. Although the overall risk of CHD and CVD was lower in diabetic women compared with women with CHD, the risk of fatal CHD, fatal CVD, and all-cause mortality was similar (hazard ratio [95% confidence interval]: 0.85 [0.65–1.12], 0.99 [0.78–1.25], and 1.18 [0.98–1.42], respectively, after adjusting for age, lifestyle factors, CHD risk factors, statin use, and treatment assignment).

Conclusions—
In the RUTH trial, diabetes mellitus was a CHD risk equivalent in women for fatal, but not nonfatal, CHD and CVD.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov/show/NCT00190593
. Unique identifier: NCT00190593.
The Effect of Graduated Compression Stockings on Long-term Outcomes After Stroke
Authors:   The CLOTS Trials Collaboration, Dennis Martin , Sandercock Peter , Reid John , Graham Catriona , Murray Gordon , Venables Graham , Rudd Anthony , Bowler Gill 
Published: March 2013

Background and Purpose—
Most randomized controlled trials of venous thromboembolism prophylaxis have focused on reduction of deep vein thrombosis, predominantly asymptomatic deep vein thrombosis, detected on imaging. We aimed to estimate the effects of graduated compression stockings on venous thromboembolism events, survival, and functional status at 6 months after stroke.

Methods—
The CLOTS Trials adopted an international multicentre, parallel group design, with central randomization and a 1:1 treatment allocation. In CLOTS Trial 1, 2518 immobile stroke patients were allocated thigh-length graduated compression stockings or not, and in CLOTS trial 2, 3014 to thigh-length or below-knee graduated compression stockings. We measured vital status, Oxford Handicap Scale, and quality of life (EQ5D-3 L) at 6 months.

Results—
We compared survival in patients enrolled in Trials 1 and 2 with a Cox proportional hazards model, including variables included in our minimization algorithm. In both trials, allocation to thigh-length graduated compression stockings was associated with a very slight, but nonsignificant, increased hazard of death in the first 6 months (Trial 1: hazard ratio, 1.087; 95% confidence interval, 0.913–1.295; and Trial 2: hazard ratio, 1.037; 95% confidence interval, 0.892–1.205). There were no statistically significant differences in venous thromboembolism events, Oxford Handicap Scale, or EQ5D-3 L between the treatment groups in CLOTS Trials 1 or 2.

Conclusions—
Although underpowered to detect clinically important effects on long-term outcomes, our results effectively exclude a >10% relative reduction in the hazard of death within 6 months associated with the use of thigh-length stockings. No other long-term benefits were apparent.
Risk of Stroke or Systemic Embolism in Atrial Fibrillation Patients Treated With Warfarin
Authors: Albertsen Ida Ehlers , Rasmussen Lars Hvilsted , Overvad Thure Filskov , Graungaard Tina , Larsen Torben Bjerregaard , Lip Gregory Y.H. 
Published: March 2013

Background and Purpose—
Although oral anticoagulants (OACs) are highly effective in reducing stroke risk in atrial fibrillation, some patients still sustain stroke despite being on an OAC. Our aim was to identify the risk factors that contribute to stroke risk in atrial fibrillation, although patients were taking OACs in a clinical trial setting.

Methods—

We identified contemporary clinical trials that investigated OACs in patients with atrial fibrillation. Event rates per year from each study and pooled event rates and relative risks, all with a 95% confidence interval, were calculated. Statistical heterogeneity was assessed using the
I
2
test.

Results—

Six trials were included in the meta-analysis, with a total of 58 883 patients randomized. Characteristics associated with a higher relative risk of stroke while on an OAC included age ≥75 years (relative risk, 1.46 [95% confidence interval, 1.25–1.69]), female sex (1.30 [1.15–1.49]), previous stroke/transient ischemic attack (1.85 [1.32–2.60]), vitamin K-antagonist naive status (for vitamin K antagonist experienced, 0.85 [0.74–0.97]), moderate and severe renal impairment (1.54 [1.30–1.81] and 2.22 [1.85–2.66], respectively, compared with normal renal function), previous aspirin use (1.19 [1.04–1.37]), Asian race (1.70 [1.42–2.03]), and a CHADS
2
score of ≥3 (1.64 [1.18–2.27]).

Conclusions—

Stroke rates are higher on OACs with some patient clinical characteristics, that is, older age, female sex, previous stroke/transient ischemic attack, vitamin K-antagonist naive status, renal impairment, previous aspirin use, and higher CHADS
2
score. The identified risk factors for stroke while on an OAC could potentially be used to consider a risk assessment tool to flag up high-risk patients while on an OAC (in this case, warfarin). Whether these risk factors apply to novel OACs is uncertain.
Adelaide Stroke Incidence Study
Authors: Leyden James M. , Kleinig Timothy J. , Newbury Jonathan , Castle Sally , Cranefield Jennifer , Anderson Craig S. , Crotty Maria , Whitford Deirdre , Jannes Jim , Lee Andrew , Greenhill Jennene 
Published: March 2013

Background and Purpose—
Stroke incidence rates are in flux worldwide because of evolving risk factor prevalence, risk factor control, and population aging. Adelaide Stroke Incidence Study was performed to determine the incidence of strokes and stroke subtypes in a relatively elderly population of 148 000 people in the Western suburbs of Adelaide.

Methods—
All suspected strokes were identified and assessed in a 12-month period from 2009 to 2010. Standard definitions for stroke and stroke fatality were used. Ischemic stroke pathogenesis was classified by the Trial of ORG 10172 in Acute Stroke Treatment criteria.

Results—
There were 318 stroke events recorded in 301 individuals; 238 (75%) were first-in-lifetime events. Crude incidence rates for first-ever strokes were 161 per 100 000 per year overall (95% confidence interval [CI], 141–183), 176 for men (95% CI, 147–201), and 146 for women (95% CI, 120–176). Adjusted to the world population rates were 76 overall (95% CI, 59–94), 91 for men (95% CI, 73–112), and 61 for women (95% CI, 47–78). The 28-day case fatality rate for first-ever stroke was 19% (95% CI, 14–24); the majority were ischemic (84% [95% CI, 78–88]). Intracerebral hemorrhage comprised 11% (8–16), subarachnoid hemorrhage 3% (1–6), and 3% (1–6) were undetermined. Of the 258 ischemic strokes, 42% (95% CI, 36–49) were of cardioembolic pathogenesis. Atrial fibrillation accounted for 36% of all ischemic strokes, of which 85% were inadequately anticoagulated.

Conclusions—
Stroke incidence in Adelaide has not increased compared with previous Australian studies, despite the aging population. Cardioembolic strokes are becoming a higher proportion of all ischemic strokes.