Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma
Xiao Hong Ma,Sheng Fu Piao,Souvik Dey,Quentin McAfee,Giorgos C. Karakousis,Jessie Villanueva,Lori S. Hart,Samuel M. Levi,Janice Hu,Gao Zhang,Rossitza Lazova,Vincent Klump,John M. Pawelek,Xiaowei Xu,Wei Xu,Lynn M. Schuchter,Michael A. Davies,Meenhard Herlyn,Jeffrey D. Winkler,Constantinos Koumenis,Ravi K. Amaravadi +20 more
TLDR
Using tumor biopsies from BRAF(V600E) melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, it is found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline and a rationale for combination approaches targeting this resistance pathway is provided.Abstract:
Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAFV600E melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAFV600E melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.read more
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Targeting autophagy in cancer
TL;DR: A way forward is suggested for the effective targeting of autophagy by understanding the context-dependent roles of autophile and by capitalizing on modern approaches to clinical trial design.
Journal ArticleDOI
The role for autophagy in cancer.
TL;DR: Mechanisms by which autophagy promotes cancer include suppressing induction of the p53 tumor suppressor protein and maintaining metabolic function of mitochondria.
Journal ArticleDOI
Autophagy in malignant transformation and cancer progression
Lorenzo Galluzzi,Federico Pietrocola,Federico Pietrocola,José Manuel Bravo-San Pedro,José Manuel Bravo-San Pedro,Ravi K. Amaravadi,Eric H. Baehrecke,Francesco Cecconi,Patrice Codogno,Jayanta Debnath,David A. Gewirtz,Vassiliki Karantza,Alec C. Kimmelman,Sharad Kumar,Beth Levine,Maria Chiara Maiuri,Maria Chiara Maiuri,Seamus J. Martin,Josef M. Penninger,Mauro Piacentini,David C. Rubinsztein,Hans-Uwe Simon,Anne Simonsen,Andrew Thorburn,Guillermo Velasco,Kevin M. Ryan,Guido Kroemer +26 more
TL;DR: The differential impact of autophagy on distinct phases of tumorigenesis is discussed and the implications of this concept for the use of Autophagy modulators in cancer therapy are discussed.
Journal ArticleDOI
The impact of the endoplasmic reticulum protein-folding environment on cancer development.
Miao Wang,Randal J. Kaufman +1 more
TL;DR: The impact of ER stress and UPR activation on every aspect of cancer is summarized and outstanding questions for which answers will pave the way for therapeutics are discussed.
Journal ArticleDOI
UPR, autophagy, and mitochondria crosstalk underlies the ER stress response
Daniela Senft,Ze'ev Ronai +1 more
TL;DR: Crosstalk among the fundamental processes governing ERS responses is summarized, which shows how activation of the unfolded protein response could trigger changes in mitochondrial function or autophagy, which could modulate the UPR, exemplifying crosstalks processes.
References
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Platanias,Stefanie Pöggeler,Marc Poirot,Angelo Poletti,Christian Poüs,Mercedes Pozuelo-Rubio,Mette Prætorius-Ibba,Anil Prasad,Mark Prescott,Muriel Priault,Nathalie Produit-Zengaffinen,Ann Progulske-Fox,Tassula Proikas-Cezanne,Serge Przedborski,Karin Przyklenk,Rosa Puertollano,Julien Puyal,Shu-Bing Qian,Liang Qin,Zheng-Hong Qin,Susan E. Quaggin,Nina Raben,Hannah Rabinowich,Simon W. Rabkin,Irfan Rahman,Abdelhaq Rami,Georg Ramm,Glenn Randall,Felix Randow,V. Ashutosh Rao,Jeffrey C. Rathmell,Brinda Ravikumar,Swapan K. Ray,Bruce H. Reed,John C. Reed,Fulvio Reggiori,Anne Régnier-Vigouroux,Anne Régnier-Vigouroux,Andreas S. Reichert,John J. Reiners,Russel J. Reiter,Jun Ren,José L. Revuelta,Christopher J. Rhodes,Konstantinos Ritis,Elizete Rizzo,Jeffrey Robbins,Michel Roberge,Hernan Roca,Maria Carmela Roccheri,Stéphane Rocchi,H. Peter Rodemann,Santiago Rodríguez de Córdoba,Bärbel Rohrer,Igor B. Roninson,Kirill V. Rosen,Magdalena Rost-Roszkowska,Mustapha Rouis,Kasper M.A. Rouschop,Francesca Rovetta,Brian P. Rubin,David C. Rubinsztein,Klaus Ruckdeschel,Edmund B. Rucker,Assaf Rudich,Emil Rudolf,Nelson Ruiz-Opazo,Rossella Russo,Tor Erik Rusten,Kevin M. Ryan,Stefan W. Ryter,David M. Sabatini,Junichi Sadoshima,Tapas Saha,Tatsuya Saitoh,Hiroshi Sakagami,Yasuyoshi Sakai,Ghasem Hosseini Salekdeh,Paolo Salomoni,Paul M. Salvaterra,Guy S. Salvesen,Rosa Salvioli,Anthony Sanchez,José Antonio Sánchez-Alcázar,Ricardo Sánchez-Prieto,Marco Sandri,Uma Sankar,Poonam Sansanwal,Laura Santambrogio,Shweta Saran,Sovan Sarkar,Minnie M. Sarwal,Chihiro Sasakawa,Ausra Sasnauskiene,Miklós Sass,Ken Sato,Miyuki Sato,Anthony H.V. Schapira,Michael Scharl,Hermann M. Schätzl,Wiep Scheper,Stefano Schiaffino,Claudio Schneider,Marion Schneider,Regine Schneider-Stock,Patricia V. Schoenlein,Daniel F. Schorderet,Christoph Schüller,Gary K. Schwartz,Luca Scorrano,Linda Sealy,Per Ottar Seglen,Juan Segura-Aguilar,Iban Seiliez,Oleksandr Seleverstov,Christian Sell,Jong Bok Seo,Duska Separovic,Vijayasaradhi Setaluri,Takao Setoguchi,Carmine Settembre,John J. Shacka,Mala Shanmugam,Irving M. Shapiro,Eitan Shaulian,Reuben J. Shaw,James H. Shelhamer,Han-Ming Shen,Wei-Chiang Shen,Zu-Hang Sheng,Yang Shi,Kenichi Shibuya,Yoshihiro Shidoji,Jeng-Jer Shieh,Chwen Ming Shih,Yohta Shimada,Shigeomi Shimizu,Takahiro Shintani,Orian S. Shirihai,Gordon C. Shore,Andriy A. Sibirny,Andriy A. Sibirny,Stan B. Sidhu,Beata Sikorska,Elaine C.M. Silva-Zacarin,Alison Simmons,Anna Katharina Simon,Hans-Uwe Simon,Cristiano Simone,Anne Simonsen,David A. Sinclair,Rajat Singh,Debasish Sinha,Frank A. Sinicrope,Agnieszka Sirko,Parco M. Siu,Efthimios Sivridis,Vojtech Skop,Vladimir P. Skulachev,Ruth S. Slack,Soraya S. Smaili,Duncan R. Smith,Maria S. Soengas,Thierry Soldati,Xueqin Song,Anil K. Sood,Tuck Wah Soong,Federica Sotgia,Stephen A. Spector,Stephen A. Spector,Claudia Spies,Wolfdieter Springer,Srinivasa M. Srinivasula,Leonidas Stefanis,Joan S. Steffan,Ruediger Stendel,Harald Stenmark,Anastasis Stephanou,Stephan T. Stern,Cinthya Sternberg,Björn Stork,Peter Strålfors,Carlos S. Subauste,Xinbing Sui,David Sulzer,Jiaren Sun,Shi-Yong Sun,Zhi Jun Sun,Joseph J.Y. Sung,Kuninori Suzuki,Toshihiko Suzuki,Michele S. Swanson,Charles Swanton,Sean T. Sweeney,Lai King Sy,Gyorgy Szabadkai,Ira Tabas,Heinrich Taegtmeyer,Marco Tafani,Krisztina Takács-Vellai,Yoshitaka Takano,Kaoru Takegawa,Genzou Takemura,Fumihiko Takeshita,Nicholas J. Talbot,Kevin S. W. Tan,Keiji Tanaka,Kozo Tanaka,Daolin Tang,Dingzhong Tang,Isei Tanida,Bakhos A. Tannous,Nektarios Tavernarakis,Graham S. Taylor,Gregory A. Taylor,J. Paul Taylor,Ance S. Terada,Alexei Terman,Gianluca Tettamanti,Karin Thevissen,Craig B. Thompson,Andrew Thorburn,Michael Thumm,Feng Feng Tian,Yuan Tian,Glauco P. Tocchini-Valentini,Aviva M. Tolkovsky,Yasuhiko Tomino,Lars Tönges,Sharon A. Tooze,Cathy Tournier,John Tower,Roberto Towns,Vladimir Trajkovic,Leonardo H. Travassos,Ting Fen Tsai,Mario P. Tschan,Takeshi Tsubata,Allan Tsung,Boris Turk,Lorianne S. Turner,Suresh C. Tyagi,Yasuo Uchiyama,Takashi Ueno,Midori Umekawa,Rika Umemiya-Shirafuji,Vivek K. Unni,Maria I. Vaccaro,Enza Maria Valente,Enza Maria Valente,Greet Van den Berghe,Ida J. van der Klei,Wouter G. van Doorn,Linda F. van Dyk,Marjolein van Egmond,Leo A. van Grunsven,Peter Vandenabeele,Wim Vandenberghe,Ilse Vanhorebeek,Eva C. Vaquero,Guillermo Velasco,Tibor Vellai,Jose Miguel Vicencio,Richard D. Vierstra,Miquel Vila,Cécile Vindis,Cécile Vindis,Giampietro Viola,Maria Teresa Viscomi,Olga V. Voitsekhovskaja,Clarissa von Haefen,Marcela Votruba,Keiji Wada,Richard Wade-Martins,Cheryl L. Walker,Craig M. Walsh,Jochen Walter,Xiang Bo Wan,Aimin Wang,Chenguang Wang,Dawei Wang,Fan Wang,Fen Wang,Guanghui Wang,Haichao Wang,Hong Gang Wang,Horng-Dar Wang,Jin Wang,Ke Wang,Mei Wang,Richard C. 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Clonogenic assay of cells in vitro
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