Oncogenic KRAS recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis
作者：Michael P Kim, Xinqun Li, Jenying Deng, Yun Zhang, Bingbing Dai, Kendra L Allton, Tara G. Hughes, Christian Siangco, Jithesh J. Augustine, Ya'an Kang, Joy M McDaniel, Shunbin Xiong, Eugene J Koay, Florencia McAllister, Christopher A. Bristow, Timothy P. Heffernan, Anirban Maitra, Bin Liu, Michelle C. Barton, Amanda R Wasylishen, Jason B. Fleming, Guillermina Lozano
期刊：Cancer Discovery
發(fā)表時間：2021/03/26
摘要：
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal and characterized by early metastasis. Oncogenic KRAS mutations prevail in 95% of PDAC tumors and co-occur with genetic alterations in the TP53 tumor suppressor in nearly 70% of patients. Most TP53 alterations are missense mutations that exhibit gain-of-function phenotypes that include increased invasiveness and metastasis yet the extent of direct cooperation between KRAS effectors and mutant p53 remains largely undefined. We show that oncogenic KRAS effectors activate cyclic AMP responsive element binding protein 1 (CREB1) to allow physical interactions with mutant p53 that hyperactivate multiple pro-metastatic transcriptional networks. Specifically, mutant p53 and CREB1 upregulate the pro-metastatic, pioneer transcription factor, FOXA1, activating its transcriptional network while promoting Wnt/B-catenin signaling, together driving PDAC metastasis. Pharmacologic CREB1 inhibition dramatically reduced FOXA1 and B-catenin expression and dampened PDAC metastasis, identifying a new therapeutic strategy to disrupt cooperation between oncogenic KRAS and mutant p53 to mitigate metastasis.
KRAS和p53蛋白是兩個“臭名昭著”的“不可成藥”靶點，雖然在這兩個蛋白上的突變在癌癥患者中最為常見，但是傳統(tǒng)的小分子藥物很難有效靶向KRAS或p53，直到最近幾年，針對KRAS G12C 突變體的靶向療法開發(fā)才獲得突破，然而KRAS G12C突變在胰腺癌中只占2%，因此胰腺癌患者獲益有限。目前仍然缺乏靶向p53的有效手段，MD安德森癌癥中心的研究團隊想要找到KRAS和p53介導的信號通路中的共同靶點，開發(fā)更為有效的胰腺癌療法。在這項研究中，科學家們設計了一種小鼠模型，在胰腺癌腫瘤細胞中同時表達致癌KRAS突變體和p53突變體，同時并不改變腫瘤周圍的微環(huán)境。在這一模型中，研究人員發(fā)現(xiàn)，與p53缺失的小鼠相比，攜帶雙重突變體的小鼠的轉移瘤數(shù)目提高了一倍，這意味著兩種突變蛋白之間的相互作用顯著提高了腫瘤轉移的潛力。
進一步的研究發(fā)現(xiàn)，KRAS突變體能夠激活稱為CREB1的轉錄因子，而它能夠直接與突變p53相互作用，導致上百種基因表達的異常。其中促進癌癥轉移的轉錄因子FOXA1的表達上調會激活Wnt/β連環(huán)蛋白信號通路，促進腫瘤轉移。發(fā)現(xiàn)CREB1是KRAS和p53突變體之間相互作用的關鍵因子之后，研究人員用靶向CREB1的小分子藥物抑制它的活性，在小鼠模型中，這導致FOXA1，β連環(huán)蛋白和相關靶點基因表達水平的降低，同時減少了腫瘤轉移的發(fā)生。這些發(fā)現(xiàn)意味著靶向CREB1可能成為在胰腺癌中阻斷KRAS和p53突變體導致的腫瘤轉移的有效策略。
▲這一研究的負責人，MD安德森癌癥中心的Michael Kim博士（圖片來源：CREDIT: MD ANDERSON CANCER CENTER）
“據(jù)我們所知，這是首次顯示這兩個重要致癌基因通過相互作用驅動腫瘤生長和轉移的研究。”這一研究的負責人，MD安德森癌癥中心的Michael Kim博士說，“這一相互作用節(jié)點的發(fā)現(xiàn)意味著我們應該更加關注CREB1這一靶點，開發(fā)可能改善患者結果的療法。由于KRAS和TP53基因突變在人類癌癥中出現(xiàn)頻率很高，我們研究的潛在意義可能遠遠超出胰腺癌。”參考資料：
[1] Mutant KRAS and p53 cooperate to drive pancreatic cancer metastasis. Retrieved April 20, 2021, from https://www.eurekalert.org/pub_releases/2021-04/uotm-mka040721.php
[2] AACR: MD Anderson team uncovers new target for blocking mutant KRAS and p53 in pancreatic cancer. Retrieved April 20, 2021, from https://www.fiercebiotech.com/research/aacr-md-anderson-team-uncovers-new-target-for-blocking-mutant-kras-and-p53-pancreatic
[3] Kim et al., (2021). Oncogenic KRAS recruits an expansive transcriptional network through mutant p53 to drive pancreatic cancer metastasis. Cancer Discovery, DOI: 10.1158/2159-8290.CD-20-1228
