KRAS Mutation in PDAC: History
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Subjects: Genetics & Heredity | Oncology
Contributor:
Meichen Gu

绝大多数胰腺导管腺癌患者的肿瘤中含有 KRAS 突变。在功能上，突变的KRAS不仅致力于肿瘤细胞的增殖，存活和侵袭性，而且还导致该癌症的免疫抑制。 

  • KRAS gene
  • pancreatic ductal adenocarcinoma
  • cancer immunity
  • immune checkpoint blockade

一、简介

在人类中，胰腺导管腺癌（PDAC）患者通常预后较差。肿瘤中现有的免疫环境会影响ICB治疗的有效性[ 6 ]。在 PDAC 中，肿瘤环境通常具有免疫抑制作用 [ 7 ]。最近，人们已经认识到驱动癌基因在癌症免疫状态中发挥着令人信服的作用 [ 8 ]。在 PDAC 中，Kirsten 大鼠肉瘤病毒癌基因同源物 ( KRAS ) 基因发生广泛突变 [ 9 ]。PDAC 中的KRAS突变包括由密码子 12 或密码子 13 中的错义突变引起的突变，导致原始甘氨酸 (G) 被其他氨基酸取代，从而导致持续激活在这种情况下的KRAS蛋白 [ 9 ]。的KRAS突变作为驾驶员原因PDAC发生，发展与其它基因，如肿瘤蛋白P53基因（的伴随灭活TP53），细胞周期蛋白依赖性激酶抑制剂2A基因（CDKN2A）和SMAD家族成员4基因（SMAD4） [ 10 , 11 ]（图 1）。在这个过程中，KRAS突变也会导致下游通路的激活，这些通路可以提高癌细胞的存活、增殖、免疫逃避和耐药性[ 7 , 9 ]。关于 PDAC 中的免疫抑制，KRAS突变利用多种途径来实现这一目标，例如激活 yes 相关蛋白 (YAP)-tafazzin (TAZ) 通路及其下游 Janus 激酶信号转导和转录激活因子 3 (JAK-STAT3) 信号传导 [ 12 ]，诱导细胞通过重新编程的葡萄糖代谢[自噬相关的主要组织相容性复合体I（MHC-I）降解13，14 ]，并与其他的遗传改变协同（例如，TP53失活）[ 15 ]（图1）。因此，PDAC 肿瘤可以被具有促癌功能的骨髓细胞浸润，例如中性粒细胞、骨髓源性抑制细胞 (MDSCs) 和 M2 样巨噬细胞 [ 7]]。

癌症 13 02429 g001 550

图 1. PDAC 肿瘤中KRAS突变诱导生长和免疫抑制的注释图。该KRAS突变主要通过以下途径在 PDAC 肿瘤中引起抑制环境，例如激活丝裂原活化蛋白激酶 (MAPK) 和磷脂酰肌醇 3-激酶 (PI3K)-Akt，激活 YAP-TAZ 和 JAK-STAT3，以及诱导PDAC细胞中的细胞自噬和代谢重编程。在这种情况下，PDAC细胞的存活和增殖会加速，肿瘤细胞的过度生长会导致肿瘤内缺氧，进而激活缺氧诱导因子1（HIF-1）α，上调编码基因的表达。血管内皮生长因子 (VEGF) 通过 PDAC 细胞。VEGF 是一种有效的细胞因子，可诱导血管生成和免疫逃避（例如，程序性死亡配体 1 (PD-L1) 上调和杀伤肿瘤性 T 细胞耗竭）。同时，PDAC细胞可以增加抑制性细胞因子和趋化因子的产生，例如白介素4（IL-4），IL-6，IL-13，巨噬细胞集落刺激因子1（CSF-1）和单核细胞趋化蛋白1（MCP-1） )，然后招募并增加免疫浸润物的存活和抑制功能，包括癌症相关成纤维细胞 (CAF)、MDSC、M2 样肿瘤相关巨噬细胞 (TAM)、产生吲哚胺 2, 3-双加氧酶 (IDO) 的树突细胞(DC) 和调节性 T 细胞 (Treg 细胞)。在这种情况下，抑制性细胞的过载将增加抑制性细胞因子和趋化因子的局部水平，例如转化生长因子-β (TGF-β)、IDO、IL-10、粒细胞-巨噬细胞集落刺激因子 (GM-CSF) , 趋化因子 CXC 基序配体 1 (CXCL1)、CXCL8、CXCL12 和 CXCL13，从而加强肿瘤中的免疫抑制（例如，杀瘤性 T 细胞排除）。与KRAS突变，基因和分子水平的其他改变，例如肝激酶 B1 基因 ( LKB1 ) 失活、TP53失活、磷酸酶和张力蛋白同源基因 ( PTEN ) 失活、粘着斑激酶 (FAK) 激活、磷脂酰肌醇 4, 5-二磷酸3-激酶催化亚基 α (PIK3CA) 激活或 Wingless/整合 (WNT) 激活也有助于肿瘤生长（例如 PDAC 细胞存活、增殖和侵袭）和免疫逃避（PD-L1 上调）。

2. KRAS突变在 PDAC 中的致癌作用

人PDAC只具有KRAS突变而不是神经母细胞瘤RAS病毒癌基因同系物基因（NRAS）或哈维大鼠肉瘤病毒原癌基因同源基因（HRAS）突变[ 9 ]。总体而言，97.7% 的 PDAC 病例被检测到具有KRAS突变 [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95]。G12D、G12V和G12R是PDAC中三种最常见的KRAS突变错义形式，其中以G12D错义突变最为常见[ 9 ]（表1）。生理上，正常的KRAS蛋白具有 GTPase 活性，但这些错义变体会产生与 GTP 稳定结合的 KRAS 蛋白，从而组成性激活 MAPK 和 PI3K-Akt 通路，这两条经典通路负责维持细胞存活和增殖 [ 35 ]（图 1）。

表 1. KRAS 突变型腺癌免疫相关特征的比较。
  癌症 数模转换器 CRAC LUAC
字符 [参考]  
KRAS突变的流行率 97.7% [ 9 ] 44.7% [ 9 ] 30.9% [ 9 ]
KRAS 中最热门的错义突变 G12D [ 9 ] G12D [ 9 ] G12C [ 9 ]
Sensitive to glucose restriction vs. KRASwt Yes [19] Yes [20] No [21]
Common alteration with KRAS TP53 inactivation [10] TP53 and APC inactivation [22] TP53 or LKB1 inactivation [23]
General milieu of KRAS-mutant tumors Immune-cold [7] Immune-cold [24] KRAS-only: immune-cold or hot [23]
TP53 inactivation: immune-hot [23]
LKB1 inactivation: immune-cold [23]
Number/function of tumoricidal T cells in KRAS-mutant tumors Decrease/Decrease [7] Decrease/Decrease [24] KRAS-only: slight increase/decrease [23]
TP53 inactivation: significant increase/decrease [23]
LKB1 inactivation: significant decrease/decrease [23]
Major type of immune infiltrates in KRAS-mutant tumors Myeloid suppressive cell [7] Myeloid suppressive cell [24] KRAS-only: T cell, macrophage, neutrophil [23]
TP53 inactivation: CD8+ T cell, CD45RO+ T cell [23]
LKB1 inactivation: myeloid suppressive cell [23]
Common presentation of the ICB therapy biomarker if KRAS mutation pMMR/MSS [25] pMMR/MSS [26] KRAS-only: PD-L1 expression ↑ [23]
TP53 inactivation: PD-L1 expression ↑↑ [23]
LKB1 inactivation: PD-L1 expression ↓↓ [23]
Biomarker associated with the effectiveness of ICB therapy dMMR/MSI-H [4] dMMR/MSI-H [27] PD-L1 [23]
Prevalence of dMMR/MSI-H in all cases 1~2% [25] 14% [26] NM
Prevalence of positive expression of PD-L1 by tumor cells NM NM Among KRAS-only tumors: 37.5% [23]
Among TP53 inactivation tumors: 68.8% [23]
Among LKB1 inactivation tumors: 10% [23]
General response to monotherapy using ICB drugs Poor [5] Poor [28] KRAS-only tumor: Fair [23]
TP53 inactivation tumor: Excellent [23]
LKB1 inactivation tumor: Poor [23]
Core molecular events associated with KRAS mutation-induced immunosuppression 1. YAP-TAZ activation [12];
2. JAK-STAT3 activation [12];
3. Metabolic reprogramming of glucose and cell autophagy [13,14];
4. In concert with other events, TP53 inactivation [15], LKB1 mutation [29,30], PTEN loss [29,30], WNT/β-catenin activation [29,30], FAK activation [29,30], PIK3CA activation [29,30] and MYC activation [29,30];		 1. In concert with APC and TP53 inactivation: TGF-β1 upregulation and EMT [31];
2. TGF-β-induced immune suppression [32];
3. IRF2 inactivation [24,33];
4. Metabolic dysregulation in glucose, glutamine, fatty acid and lipid [26,34];
5. MAPK and HIF-1-related cascade activation [34];		 1. ERK activation-induced PD-L1 upregulation [23]
2. Metabolic reprogramming of glucose [21]
3. In concert with LKB1 inactivation: strengthening metabolic reprogramming of glucose and JAK-STAT3 activation [23]
PDAC: pancreatic ductal adenocarcinoma; CRAC: colorectal adenocarcinoma; EMT: epithelial-mesenchymal transition; LUAC: lung adenocarcinoma; APC: adenomatous polyposis coli protein; pMMR: proficient mismatch repair; MAPK: mitogen-activated protein kinase; MSS: microsatellite stability; dMMR: deficient mismatch repair; MSI-H: high microsatellite instability; ICB: immune checkpoint blockade; NM: no mention; PD-L1: programmed death-ligand 1; TP53: tumor protein P53 gene; LKB1: liver kinase B1 gene.

3. The KRAS Mutation and Immune Environment in PDAC

In addition to impacting cell survival, proliferation and nutrient metabolism during pancreatic carcinogenesis, KRAS mutations also function in controlling the cancer immune environment. In addition, in mice bearing pancreatitis-induced ADM, KLF5 deficiency was revealed to suppress STAT3 activation [36]. In another mechanism, KRASG12D mutation-induced upregulation of YAP and TAZ was revealed to potently activate the downstream JAK-STAT3 pathway during pancreatic carcinogenesis in mice [12] (Figure 1). In fact, mutant KRAS can cooperate with extracellular stimuli, such as inflammation, the gut microbiota and gastrointestinal peptides, to persistently activate downstream YAP-TAZ signaling, which undermines immune surveillance against PDAC cells in addition to improving their proliferation, invasion, survival and metabolism [42]. In PDAC, a high expression of YAP was revealed to correlate with a poor histological grade of tumor cells [43], a high risk of metastasis and a poor prognosis of patients [44].

Mechanistically, KRAS mutation-induced activation of YAP enables PDAC cells to release IL-4, IL-6, IL-13, MCP-1 and CSF-1, which promote the recruitment of tumor-associated macrophages (TAMs) into tumors and induce them to proliferate and polarize into an M2-like phenotype [45] (Figure 1). In addition, the prevalence of TP53 inactivation is only second to the prevalence of KRAS mutation in PDAC [10], meaning that a large portion of patients concomitantly harbor KRAS mutation and TP53 inactivation [10].

In concert with the KRAS mutation, alterations in environmental, genetic and molecular levels, such as hypoxia, LKB1 mutation, PTEN loss, PIK3CA activation, WNT/β-catenin activation, FAK activation and MYC proto-oncogene (MYC) activation also contribute to immune suppression in PDAC tumors [29,30] (Figure 1).

4. Current Status of Immune Checkpoint Blockade Therapy for PDAC

Since the tumoral milieu of PDAC is immunosuppressive, ICB therapy is anticipated to have low effectiveness in this cancer. In fact, several lines of clinical data have confirmed this speculation, and the effectiveness of monotherapy by using ICB drugs in patients with metastatic PDAC remains disappointing [5]. ICB drugs are not effective in significantly shrinking the size of PDAC tumors when used as a second- or later-line therapy regardless of whether they are used alone or in combination with radiotherapy or chemotherapy (Table 2).

Table 2. The effectiveness of ICB therapy on PDAC.
Author [Ref.] Year Phase Patient No. ICB Drug Other Treatment ORR
• First-line therapy
Aglietta M, et al. [62] 2014 I 34 Tremelimumab Gemcitabine 10.5%
Wainberg ZA, et al. [63] 2019 I 50 Nivolumab Gemcitabine + Nab- paclitaxel 18%
Wainberg ZA, et al. [64] 2017 I 17 Nivolumab Gemcitabine + Nab- paclitaxel 50%
Renouf, et al. [65] 2018 II 11 Durvalumab + Tremelimumab Gemcitabine + Nab-paclitaxel 73%
Borazanci, et al. [66] 2018 II 11 Nivolumab Gemcitabine + Nab-paclitaxel + Cisplatin + Paricalcitol 80%
• Second- or later-line therapy
Luke JJ, et al. [57] 2018 I 3 Pembrolizumab SBRT: 30–50 Gy for 2–4 metastatic lesions NR
O’Reilly EM, et al. [56] 2019 II Arm A: 32
Arm B: 32		 Durvalumab
Durvalumab + Tremelimumab		 No 0%
3.1%
Xie C, et al. [58] 2020 I Arm A1: 14
Arm A2: 10
Arm B1: 19
Arm B2: 16		 Durvalumab
Durvalumab
Durvalumab + Tremelimumab
Durvalumab + Tremelimumab		 SBRT: 8 Gy/1 fraction
SBRT: 25 Gy/5 fractions
SBRT: 8 Gy/1 fraction
SBRT: 25 Gy/5 fractions		 5.1% A
Weiss GJ, et al. [60] 2017 I 11 Pembrolizumab Gemcitabine (Gem)-based chemotherapy 18.2%
Kamath SD, et al. [61] 2020 I 21 B Arm A: Ipilimumab 3 mg/kg
Arm B: Ipilimumab 3 mg/kg
Arm C: Ipilimumab 6 mg/kg		 Gem 750 mg/m2
Gem 1g/m2
Gem 1g/m2		 14% C
Abbreviation: PDAC: pancreatic ductal adenocarcinoma; ORR: objective response rate; SBRT: A: The total ORR of four arms; B: 67% of them received at least one line of chemotherapy; C: The total ORR of three arms.

5. Conclusions

PDAC 中的肿瘤环境具有很强的免疫抑制作用，这使得使用 ICB 药物的单一疗法几乎完全无效。关于 PDAC 免疫抑制的发展，涉及多种因素。在本文中，KRAS突变已被证明是该过程的核心，因为KRAS突变可以激活 YAP-TAZ 和 JAK-STAT3 以引发免疫抑制反应，然后可以通过与TP53失活和其他遗传或分子的协调来加强这种初始信号。改动。总体而言，KRAS突变通常与 PDAC 中的肿瘤免疫抑制相关。尽管如此，在 CRAC 和 LUAC 中，KRAS突变可以以不同的方式决定癌症免疫环境。在这些癌症中，尽管KRAS突变具有共性，但免疫环境各不相同。这个概念可以用KRAS 突变体 LUAC来举例说明，它对 ICB 治疗表现出不同的反应，这取决于与KRAS突变同时发生的基因改变的类型。

This entry is adapted from the peer-reviewed paper 10.3390/cancers13102429

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