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Melanoma: HELP
Articles by Yibing Yan
Based on 9 articles published since 2009
(Why 9 articles?)
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Between 2009 and 2019, Yibing Yan wrote the following 9 articles about Melanoma.
 
+ Citations + Abstracts
1 Clinical Trial Atezolizumab plus cobimetinib and vemurafenib in BRAF-mutated melanoma patients. 2019

Sullivan, Ryan J / Hamid, Omid / Gonzalez, Rene / Infante, Jeffrey R / Patel, Manish R / Hodi, F Stephen / Lewis, Karl D / Tawbi, Hussein A / Hernandez, Genevive / Wongchenko, Matthew J / Chang, YiMeng / Roberts, Louise / Ballinger, Marcus / Yan, Yibing / Cha, Edward / Hwu, Patrick. ·Massachusetts General Hospital Cancer Center, Boston, MA, USA. rsullivan7@mgh.harvard.edu. · The Angeles Clinic and Research Institute, Los Angeles, CA, USA. · University of Colorado Cancer Center, Aurora, CO, USA. · Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA. · Sarah Cannon Research Institute/Florida Cancer Specialists & Research Institute, Sarasota, FL, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · MD Anderson Cancer Center, Houston, TX, USA. · Genentech, Inc., South San Francisco, CA, USA. ·Nat Med · Pubmed #31171876.

ABSTRACT: Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAF

2 Clinical Trial Adjuvant vemurafenib in resected, BRAF 2018

Maio, Michele / Lewis, Karl / Demidov, Lev / Mandalà, Mario / Bondarenko, Igor / Ascierto, Paolo A / Herbert, Christopher / Mackiewicz, Andrzej / Rutkowski, Piotr / Guminski, Alexander / Goodman, Grant R / Simmons, Brian / Ye, Chenglin / Yan, Yibing / Schadendorf, Dirk / Anonymous33031188. ·Division of Medical Oncology and Immunotherapy, Center for Immuno-Oncology, University Hospital of Siena, Siena, Italy. Electronic address: mmaiocro@gmail.com. · University of Colorado Comprehensive Cancer Center, Aurora, CO, USA. · N N Blokhin Russian Cancer Research Center, Ministry of Health, Moscow, Russia. · Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy. · Dnipropetrovsk State Medical Academy, Dnipropetrovsk, Ukraine. · Melanoma Unit, Cancer Immunotherapy and Innovative Therapies, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy. · Bristol Haematology and Oncology Centre, Bristol, UK. · Department of Cancer Immunology, Poznan University for Medical Sciences, Med-POLONIA, Poznan, Poland. · Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Institute-Oncology Center, Warsaw, Poland. · Melanoma Translational Research Group, Melanoma Institute Australia, Wollstonecraft, NSW, Australia. · Genentech, Inc, South San Francisco, CA, USA. · Department of Dermatology, University Hospital Essen, Essen, Germany; German Cancer Consortium, Heidelberg, Germany. ·Lancet Oncol · Pubmed #29477665.

ABSTRACT: BACKGROUND: Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAF METHODS: BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAF FINDINGS: The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. INTERPRETATION: The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAF FUNDING: F Hoffman-La Roche Ltd.

3 Clinical Trial Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib. 2018

Wongchenko, Matthew J / Ribas, Antoni / Dréno, Brigitte / Ascierto, Paolo A / McArthur, Grant A / Gallo, Jorge D / Rooney, Isabelle A / Hsu, Jessie / Koeppen, Hartmut / Yan, Yibing / Larkin, James. ·Genentech, Inc., South San Francisco, CA, USA. · Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA. · Nantes University, Nantes, France. · Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Naples, Italy. · Peter MacCallum Cancer Centre, East Melbourne, VIC., Australia. · University of Melbourne, Parkville, VIC., Australia. · F. Hoffmann-La Roche Ltd, Basel, Switzerland. · The Royal Marsden NHS Foundation Trust, London, UK. ·Pigment Cell Melanoma Res · Pubmed #29156488.

ABSTRACT: The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1

4 Clinical Trial Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. 2016

Ascierto, Paolo A / McArthur, Grant A / Dréno, Brigitte / Atkinson, Victoria / Liszkay, Gabrielle / Di Giacomo, Anna Maria / Mandalà, Mario / Demidov, Lev / Stroyakovskiy, Daniil / Thomas, Luc / de la Cruz-Merino, Luis / Dutriaux, Caroline / Garbe, Claus / Yan, Yibing / Wongchenko, Matthew / Chang, Ilsung / Hsu, Jessie J / Koralek, Daniel O / Rooney, Isabelle / Ribas, Antoni / Larkin, James. ·Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy. · Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia. Electronic address: grant.mcarthur@petermac.org. · Nantes University, Nantes, France. · Princess Alexandra Hospital, Woolloongabba, QLD, Australia. · National Institute of Oncology, Budapest, Hungary. · Azienda Ospedaliera Universitaria Senese, Siena, Italy. · Papa Giovanni XXIII Hospital, Bergamo, Italy. · N N Blokhin Russian Cancer Research Center, Moscow, Russia. · Moscow City Oncology Hospital 62, Krasnogorsk, Russia. · Centre Hospitalier Lyon Sud, Lyon 1 University, Lyon, France; Lyons Cancer Research Center, Lyon, France. · Hospital Universitario Virgen Macarena, Seville, Spain. · Hôpital Saint André, Bordeaux, France. · University of Tübingen, Tübingen, Germany. · Genentech Inc, South San Francisco, CA, USA. · Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles, CA, USA. · Royal Marsden NHS Foundation Trust, London, UK. ·Lancet Oncol · Pubmed #27480103.

ABSTRACT: BACKGROUND: The combination of cobimetinib with vemurafenib improves progression-free survival compared with placebo and vemurafenib in previously untreated patients with BRAF(V600)-mutant advanced melanoma, as previously reported in the coBRIM study. In this Article, we report updated efficacy results, including overall survival and safety after longer follow-up, and selected biomarker correlative studies. METHODS: In this double-blind, randomised, placebo-controlled, multicentre study, adult patients (aged ≥18 years) with histologically confirmed BRAF(V600) mutation-positive unresectable stage IIIC or stage IV melanoma were randomly assigned (1:1) using an interactive response system to receive cobimetinib (60 mg once daily for 21 days followed by a 7-day rest period in each 28-day cycle) or placebo, in combination with oral vemurafenib (960 mg twice daily). Progression-free and overall survival were primary and secondary endpoints, respectively; all analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01689519, and is ongoing but no longer recruiting participants. FINDINGS: Between Jan 8, 2013, and Jan 31, 2014, 495 eligible adult patients were enrolled and randomly assigned to the cobimetinib plus vemurafenib group (n=247) or placebo plus vemurafenib group (n=248). At a median follow-up of 14·2 months (IQR 8·5-17·3), the updated investigator-assessed median progression-free survival was 12·3 months (95% CI 9·5-13·4) for cobimetinib and vemurafenib versus 7·2 months (5·6-7·5) for placebo and vemurafenib (HR 0·58 [95% CI 0·46-0·72], p<0·0001). The final analysis for overall survival occurred when 255 (52%) patients had died (Aug 28, 2015). Median overall survival was 22·3 months (95% CI 20·3-not estimable) for cobimetinib and vemurafenib versus 17·4 months (95% CI 15·0-19·8) for placebo and vemurafenib (HR 0·70, 95% CI 0·55-0·90; p=0·005). The safety profile for cobimetinib and vemurafenib was tolerable and manageable, and no new safety signals were observed with longer follow-up. The most common grade 3-4 adverse events occurring at a higher frequency in patients in the cobimetinib and vemurafenib group compared with the vemurafenib group were γ-glutamyl transferase increase (36 [15%] in the cobimetinib and vemurafenib group vs 25 [10%] in the placebo and vemurafenib group), blood creatine phosphokinase increase (30 [12%] vs one [<1%]), and alanine transaminase increase (28 [11%] vs 15 [6%]). Serious adverse events occurred in 92 patients (37%) in the cobimetinib and vemurafenib group and 69 patients (28%) in the vemurafenib group. Pyrexia (six patients [2%]) and dehydration (five patients [2%]) were the most common serious adverse events reported in the cobimetinib and vemurafenib group. A total of 259 patients have died: 117 (47%) in the cobimetinib and vemurafenib group and 142 (58%) in the vemurafenib group. The primary cause of death was disease progression in most patients: 109 (93%) of 117 in the cobimetinib and vemurafenib group and 133 (94%) of 142 in the vemurafenib group. INTERPRETATION: These data confirm the clinical benefit of cobimetinib combined with vemurafenib and support the use of the combination as a standard first-line approach to improve survival in patients with advanced BRAF(V600)-mutant melanoma. FUNDING: F Hoffmann-La Roche-Genentech.

5 Clinical Trial Impact of MET expression on outcome in BRAF(V600E/K) advanced melanoma. 2013

Jubb, Adrian M / Ribas, Antoni / Sosman, Jeffrey A / McArthur, Grant A / Yan, Yibing / Rost, Sandra / Zhao, Sherry / Koeppen, Hartmut. ·Product Development-Oncology, Genentech Inc., South San Francisco, CA, USA. ·Histopathology · Pubmed #23802768.

ABSTRACT: AIMS: Preclinical data suggest that signalling through the HGF-MET pathway may confer resistance to BRAF inhibition in BRAF(V600E/K) melanoma. Therefore, blockade of HGF-MET signalling might be a valid therapeutic strategy, in combination with BRAF inhibition, in BRAF(V600E/K) melanoma. The aim of this study was to investigate the clinical relevance of these observations by evaluating the survival impact of MET expression in patients with BRAF(V600E/K) advanced melanoma treated with vemurafenib. METHODS AND RESULTS: Formalin-fixed tissue blocks were obtained of tumours from patients enrolled in the BRIM2 (n = 59) and BRIM3 (n = 150) trials of vemurafenib in advanced BRAF(V600E/K) melanoma. Immunohistochemistry for MET (SP44 rabbit monoclonal antibody) was performed with a highly validated assay and clinically validated scoring system. Pretreatment MET expression was frequent at the ≥1 + cutoff (BRIM3, 31%; BRIM2, 49%), but relatively infrequent at the ≥2 + cutoff (BRIM3, 9%; BRIM2, 19%). Retrospective subset analyses showed that, irrespective of the cutoff used or the treatment arm, MET expression did not show prognostic significance, in terms of objective response rate, progression-free survival, or overall survival. CONCLUSIONS: MET is expressed in a proportion of BRAF(V600E/K) advanced melanomas. Further analyses on appropriately powered subsets are needed to determine the prognostic and predictive significance of MET in vemurafenib-treated melanoma.

6 Article Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. 2018

McQuade, Jennifer L / Daniel, Carrie R / Hess, Kenneth R / Mak, Carmen / Wang, Daniel Y / Rai, Rajat R / Park, John J / Haydu, Lauren E / Spencer, Christine / Wongchenko, Matthew / Lane, Stephen / Lee, Dung-Yang / Kaper, Mathilde / McKean, Meredith / Beckermann, Kathryn E / Rubinstein, Samuel M / Rooney, Isabelle / Musib, Luna / Budha, Nageshwar / Hsu, Jessie / Nowicki, Theodore S / Avila, Alexandre / Haas, Tomas / Puligandla, Maneka / Lee, Sandra / Fang, Shenying / Wargo, Jennifer A / Gershenwald, Jeffrey E / Lee, Jeffrey E / Hwu, Patrick / Chapman, Paul B / Sosman, Jeffrey A / Schadendorf, Dirk / Grob, Jean-Jacques / Flaherty, Keith T / Walker, Dana / Yan, Yibing / McKenna, Edward / Legos, Jeffrey J / Carlino, Matteo S / Ribas, Antoni / Kirkwood, John M / Long, Georgina V / Johnson, Douglas B / Menzies, Alexander M / Davies, Michael A. ·University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jmcquade@mdanderson.org. · University of Texas MD Anderson Cancer Center, Houston, TX, USA. · Novartis Pharmaceuticals, East Hanover, NJ, USA. · Vanderbilt University Medical Center, Nashville, TN, USA. · Melanoma Institute Australia and University of Sydney, North Sydney, NSW, Australia. · Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead NSW, Australia. · Genentech, San Francisco, CA, USA. · University of California Los Angeles Medical Center, Los Angeles, CA, USA. · Bristol-Myers Squibb, New York, NY, USA. · Dana-Farber Cancer Institute, Boston, MA, USA. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Northwestern University, Chicago, IL, USA. · University Hospital Essen and German Cancer Consortium, Essen, Germany. · Centre Hospitalo-Universitaire Timone, Aix Marseille University, Marseille, France. · Massachusetts General Hospital Cancer Center, Boston, MA, USA. · Melanoma Institute Australia and University of Sydney, North Sydney, NSW, Australia; Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead NSW, Australia. · Hillman University of Pittsburgh Medical Center Cancer Center, Pittsburgh, PA, USA. · Melanoma Institute Australia and University of Sydney, North Sydney, NSW, Australia; Royal North Shore and Mater Hospitals, St Leonards, NSW, Australia. ·Lancet Oncol · Pubmed #29449192.

ABSTRACT: BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. FINDINGS: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, p INTERPRETATION: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.

7 Article Gene Expression Profiling in 2017

Wongchenko, Matthew J / McArthur, Grant A / Dréno, Brigitte / Larkin, James / Ascierto, Paolo A / Sosman, Jeffrey / Andries, Luc / Kockx, Mark / Hurst, Stephen D / Caro, Ivor / Rooney, Isabelle / Hegde, Priti S / Molinero, Luciana / Yue, Huibin / Chang, Ilsung / Amler, Lukas / Yan, Yibing / Ribas, Antoni. ·Genentech, Inc., South San Francisco, California. wongchenko.matthew@gene.com. · Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, and University of Melbourne, Parkville, Victoria, Australia. · Nantes University, Nantes, France. · The Royal Marsden NHS Foundation Trust, London, United Kingdom. · Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy. · Vanderbilt-Ingram Cancer Center, Nashville, Tennessee. · HistoGeneX, Antwerp, Belgium. · Genentech, Inc., South San Francisco, California. · Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, Los Angeles, California. ·Clin Cancer Res · Pubmed #28536307.

ABSTRACT:

8 Article P21-activated kinase 1 (PAK1) as a therapeutic target in BRAF wild-type melanoma. 2013

Ong, Christy C / Jubb, Adrian M / Jakubiak, Diana / Zhou, Wei / Rudolph, Joachim / Haverty, Peter M / Kowanetz, Marcin / Yan, Yibing / Tremayne, Jarrod / Lisle, Richard / Harris, Adrian L / Friedman, Lori S / Belvin, Marcia / Middleton, Mark R / Blackwood, Elizabeth M / Koeppen, Hartmut / Hoeflich, Klaus P. ·Department of Translational Oncology Genentech, MS 50, 1 DNA Way, South San Francisco, CA 94080, USA. ·J Natl Cancer Inst · Pubmed #23535073.

ABSTRACT: BACKGROUND: Although remarkable clinical response rates in melanoma have been observed using vemurafenib or dabrafenib in patients with tumors carrying oncogenic mutations in BRAF, a substantial unmet medical need remains for the subset of patients with wild-type BRAF tumors. METHODS: To investigate the role of p21-activated kinases (PAKs) in melanoma, we determined PAK1 genomic copy number and protein expression for a panel of human melanoma tissues. PAK1 was inhibited in vitro and in vivo using RNA interference or PF-3758309 inhibitor treatment in a panel of melanoma cell lines with known BRAF and RAS (rat sarcoma) genotype to better understand its role in melanoma cell proliferation and migration. Tumorigenesis was assessed in vivo in female NCR nude mice and analyzed with cubic spline regression and area under the curve analyses. All statistical tests were two-sided. RESULTS: Strong cytoplasmic PAK1 protein expression was prevalent in melanomas (27%) and negatively associated with activating mutation of the BRAF oncogene (P < .001). Focal copy number gain of PAK1 at 11q13 was also observed in 9% of melanomas (n = 87; copy number ≥ 2.5) and was mutually exclusive with BRAF mutation (P < .005). Selective PAK1 inhibition attenuated signaling through mitogen-activated protein kinase (MAPK) as well as cytoskeleton-regulating pathways to modulate the proliferation and migration of BRAF wild-type melanoma cells. Treatment of BRAF wild-type melanomas with PF-3758309 PAK inhibitor decreased tumor growth for SK-MEL23 and 537MEL xenografts (91% and 63% inhibition, respectively; P < .001) and MAPK pathway activation in vivo. CONCLUSIONS: Taken together, our results provide evidence for a functional role of PAK1 in BRAF wild-type melanoma and therapeutic use of PAK inhibitors in this indication.

9 Article Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. 2012

Wilson, Timothy R / Fridlyand, Jane / Yan, Yibing / Penuel, Elicia / Burton, Luciana / Chan, Emily / Peng, Jing / Lin, Eva / Wang, Yulei / Sosman, Jeff / Ribas, Antoni / Li, Jiang / Moffat, John / Sutherlin, Daniel P / Koeppen, Hartmut / Merchant, Mark / Neve, Richard / Settleman, Jeff. ·Research Oncology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA. ·Nature · Pubmed #22763448.

ABSTRACT: Mutationally activated kinases define a clinically validated class of targets for cancer drug therapy. However, the efficacy of kinase inhibitors in patients whose tumours harbour such alleles is invariably limited by innate or acquired drug resistance. The identification of resistance mechanisms has revealed a recurrent theme—the engagement of survival signals redundant to those transduced by the targeted kinase. Cancer cells typically express multiple receptor tyrosine kinases (RTKs) that mediate signals that converge on common critical downstream cell-survival effectors—most notably, phosphatidylinositol-3-OH kinase (PI(3)K) and mitogen-activated protein kinase (MAPK). Consequently, an increase in RTK-ligand levels, through autocrine tumour-cell production, paracrine contribution from tumour stroma or systemic production, could confer resistance to inhibitors of an oncogenic kinase with a similar signalling output. Here, using a panel of kinase-'addicted' human cancer cell lines, we found that most cells can be rescued from drug sensitivity by simply exposing them to one or more RTK ligands. Among the findings with clinical implications was the observation that hepatocyte growth factor (HGF) confers resistance to the BRAF inhibitor PLX4032 (vemurafenib) in BRAF-mutant melanoma cells. These observations highlight the extensive redundancy of RTK-transduced signalling in cancer cells and the potentially broad role of widely expressed RTK ligands in innate and acquired resistance to drugs targeting oncogenic kinases.