PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas

Lu Hezhe; Liu Shujing; Zhang Gao; Wu Bin; Zhu Yueyao; Frederick Dennie T.; Hu Yi; Zhong Wenqun; Randell Sergio; Sadek Norah; Zhang Wei; Chen Gang; Cheng Chaoran; Zeng Jingwen; Wu Lawrence W.; Zhang Jie; Liu Xiaoming; Xu Wei; Krepler Clemens; Sproesser Katrin; Xiao Min; Miao Benchun; Liu Jianglan; Song Claire D.; Liu Jephrey Y.; Karakousis Giorgos C.; Schuchter Lynn M.; Lu Yiling; Mills Gordon; Cong Yusheng; Chernoff Jonathan; Guo Jun; Boland Genevieve M.; Sullivan Ryan J.; Wei Zhi; Field Jeffrey; Amaravadi Ravi K.; Flaherty Keith T.; Herlyn Meenhard; Xu Xiaowei; Guo Wei

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PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas

机译：PAK信号驱动BRAF突变型黑色素瘤中获得的对MAPK抑制剂的耐药性

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Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance(1-6). Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and beta-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.

机译：靶向BRAF抑制（BRAFi）以及BRAF和MEK抑制联合治疗（BRAFi和MEKi）治疗显着改善了转移性黑色素瘤患者的临床结局。不幸的是，这些治疗方法的有效性常常被耐药性的获得所抵消（1-6）。在这里，我们研究了对BRAFi和联合疗法产生耐药性的分子机制。与以前的研究一致，我们表明，对BRAFi的耐药性是由ERK通路重新激活介导的。然而，在许多耐药细胞系和临床样品中，对联合疗法的耐药性是由与ERK的活化无关的机制介导的。 p21激活的激酶（PAK）在具有获得性耐药性的细胞中被激活，并在介导耐药性中起关键作用。我们使用反相蛋白质阵列进行的筛选揭示了PAK介导对BRAFi和联合疗法耐药的独特机制。在抗BRAFi的细胞中，PAK磷酸化CRAF和MEK以重新激活ERK。在对联合疗法有抵抗力的细胞中，PAK调节JNK和β-catenin磷酸化以及mTOR途径活化，并抑制细胞凋亡，从而绕过ERK。总之，我们的结果提供了对获得针对当前靶向疗法的耐药性的分子机制的见解，并可能有助于指导新颖的药物开发努力来克服获得性耐药性。

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《Nature》 |2017年第7674期|133-136|共4页
作者
Lu Hezhe; Liu Shujing; Zhang Gao; Wu Bin; Zhu Yueyao; Frederick Dennie T.; Hu Yi; Zhong Wenqun; Randell Sergio; Sadek Norah; Zhang Wei; Chen Gang; Cheng Chaoran; Zeng Jingwen; Wu Lawrence W.; Zhang Jie; Liu Xiaoming; Xu Wei; Krepler Clemens; Sproesser Katrin; Xiao Min; Miao Benchun; Liu Jianglan; Song Claire D.; Liu Jephrey Y.; Karakousis Giorgos C.; Schuchter Lynn M.; Lu Yiling; Mills Gordon; Cong Yusheng; Chernoff Jonathan; Guo Jun; Boland Genevieve M.; Sullivan Ryan J.; Wei Zhi; Field Jeffrey; Amaravadi Ravi K.; Flaherty Keith T.; Herlyn Meenhard; Xu Xiaowei; Guo Wei;
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作者单位

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA;

Drexel Univ, Dept Biol, Philadelphia, PA 19104 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA;

Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA;

Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA;

Hosp Univ Penn, Dept Surg, 3400 Spruce St, Philadelphia, PA 19104 USA;

Univ Penn, Perelman Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA;

Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77054 USA;

Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77054 USA;

Hangzhou Normal Univ, Sch Med, Inst Aging Res, Hangzhou, Zhejiang, Peoples R China;

Fox Chase Canc Ctr, Canc Biol Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA;

Peking Univ, Canc Hosp & Inst, Dept Renal Canc & Melanoma, Beijing 100036, Peoples R China;

Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA;

Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA;

New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA;

Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA;

Hosp Univ Penn, Dept Surg, 3400 Spruce St, Philadelphia, PA 19104 USA;

Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA;

Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA|Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA;

Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA|Univ Penn, Perelman Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA;

Univ Penn, Dept Biol, Philadelphia, PA 19104 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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专利

1. Aberrant modulation of ribosomal protein S6 phosphorylation confers acquired resistance to MAPK pathway inhibitors in BRAF-mutant melanoma [J] . Ming-zhao Gao, Hong-bin Wang, Xiang-ling Chen, 中国药理学报：英文版 . 2019,第002期

机译：核糖体蛋白S6磷酸化的异常调节赋予BRAF突变型黑色素瘤MAPK途径抑制剂获得性耐药
2. ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma [J] . Ojha Rani, Leli Nektaria M., Onorati Angelique, Cancer discovery. . 2019,第3期

机译：MAPK途径的ER易位推动BRAF-突变体黑素瘤的治疗抗性
3. ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma (vol 9, pg 396, 2018) [J] . Ojha R., Leli N. M., Onorati A., Cancer discovery. . 2019,第7期

机译：MAPK途径的ER易位推动BRAF-突变体黑素瘤的治疗抗性（VOL 9，PG 396,2018）
4. Gene Expression Models of BRAF Inhibitor Resistance in Melanoma Predict Drug Repurposing Candidates for Novel Combination Therapies [C] . Kelly Regan, Andrew R. Stiff, William E. Carson, International Molecular Medicine Tri-Conference. . 2016

机译：黑色素瘤中BRAF抑制剂抗性的基因表达模型预测了新型组合疗法的药物重新培养候选者
5. Novel Combination Therapy to Overcome Adaptive and Acquired MAPK-inhibitor Resistance in Melanoma [D] . Hong, Aayoung 2016

机译：新型的组合疗法，克服黑色素瘤的适应性和获得性MAPK抑制剂耐药性
6. PAK Signaling Drives Acquired Drug Resistance to MAPK Inhibitors in BRAF-mutant Melanomas [O] . Hezhe Lu, Shujing Liu, Gao Zhang, -1

机译：PAK信号驱动对BRAF突变的黑素瘤中MAPK抑制剂的获得性耐药。
7. Correction: ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma [O] . 2019

机译：校正：MAPK途径的ER易位推动BRAF-突变体黑素瘤的治疗抗性

PAK signalling drives acquired drug resistance to MAPK inhibitors in BRAF-mutant melanomas

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