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(shí)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(gè)“臭名昭著”的“不可成藥”靶點(diǎn)，雖然在這兩個(gè)蛋白上的突變?cè)诎┌Y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(duì)KRAS G12C 突變體的靶向療法開發(fā)才獲得突破，然而KRAS G12C突變?cè)谝认侔┲兄徽?%，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(tuán)隊(duì)想要找到KRAS和p53介導(dǎo)的信號(hào)通路中的共同靶點(diǎn)，開發(fā)更為有效的胰腺癌療法。在這項(xiàng)研究中，科學(xué)家們?cè)O(shè)計(jì)了一種小鼠模型，在胰腺癌腫瘤細(xì)胞中同時(shí)表達(dá)致癌KRAS突變體和p53突變體，同時(shí)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(zhuǎn)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(zhuǎn)移的潛力。
進(jìn)一步的研究發(fā)現(xiàn)，KRAS突變體能夠激活稱為CREB1的轉(zhuǎn)錄因子，而它能夠直接與突變p53相互作用，導(dǎo)致上百種基因表達(dá)的異常。其中促進(jìn)癌癥轉(zhuǎn)移的轉(zhuǎn)錄因子FOXA1的表達(dá)上調(diào)會(huì)激活Wnt/β連環(huán)蛋白信號(hào)通路，促進(jìn)腫瘤轉(zhuǎn)移。發(fā)現(xiàn)CREB1是KRAS和p53突變體之間相互作用的關(guān)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(dǎo)致FOXA1，β連環(huán)蛋白和相關(guān)靶點(diǎn)基因表達(dá)水平的降低，同時(shí)減少了腫瘤轉(zhuǎn)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(dǎo)致的腫瘤轉(zhuǎn)移的有效策略。
▲這一研究的負(fù)責(zé)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(gè)重要致癌基因通過相互作用驅(qū)動(dòng)腫瘤生長(zhǎng)和轉(zhuǎn)移的研究。”這一研究的負(fù)責(zé)人，MD安德森癌癥中心的Michael Kim博士說，“這一相互作用節(jié)點(diǎn)的發(fā)現(xiàn)意味著我們應(yīng)該更加關(guān)注CREB1這一靶點(diǎn)，開發(fā)可能改善患者結(jié)果的療法。由于KRAS和TP53基因突變?cè)谌祟惏┌Y中出現(xiàn)頻率很高，我們研究的潛在意義可能遠(yuǎn)遠(yuǎn)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./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./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
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