Abstract：
Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as \"undruggable\". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a \"molecule switch\" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB). KRAS mutation shape an immune suppressive microenvironment by impeding effective T cells infiltration and recruiting suppressive immune cells including myeloid-derived suppressor cells(MDSCs), regulatory T cells(Tregs), cancer associated fibroblasts(CAFs). In immune checkpoint inhibitor(ICI) era, NSCLC patients with mutated KRAS tend to be more responsive to ICI than patients with intact KRAS. The hallmark for KRAS mutation is the existence of multiple kinds of co-mutations. Different types of co-alterations have distinct tumor microenvironment(TME) signatures and responses to ICI. TP53 co-mutation possess a \"hot\" TME and achieve higher response to immunotherapy while other loss of function mutation correlated with a \"colder\" TME and a poor outcome to ICI-based therapy. The groundbreaking discovery of KRAS G12C inhibitors significantly improved outcomes for this KRAS subtype even though efficacy was limited to NSCLC patients. KRAS G12C inhibitors also restore the suppressive TME, creating an opportunity for combinations with ICI. However, an inevitable challenge to KRAS inhibitors is drug resistance. Promising combination strategies such as combination with SHP2 is an approach deserve further exploration because of their immune modulatory effect.
摘要：
Kirsten大鼠肉瘤病毒癌基因（KRAS），第一个发现的人类癌基因，长期以来一直被认为是“不可吸毒”。KRAS突变经常发生在多种人类癌症中，包括非小细胞肺癌（NSCLC）。结直肠癌（CRC）和胰腺导管腺癌（PDAC），充当“分子开关”，决定各种致癌信号通路的激活。除了其内在的促肿瘤作用，KRAS改变还表现出独特的免疫特征,其特征在于PD-L1水平升高和高肿瘤突变负荷(TMB)。KRAS突变通过阻止有效的T细胞浸润和招募抑制性免疫细胞（包括骨髓来源的抑制细胞（MDSC））来塑造免疫抑制微环境，调节性T细胞(Tregs),癌相关成纤维细胞（CAFs）。在免疫检查点抑制剂(ICI)时代，与具有完整KRAS的患者相比,具有突变KRAS的NSCLC患者倾向于对ICI更敏感。KRAS突变的标志是存在多种共突变。不同类型的共同改变具有不同的肿瘤微环境(TME)特征和对ICI的响应。TP53共突变具有“热”TME，对免疫疗法具有更高的反应，而其他功能丧失突变与“较冷”TME和基于ICI的治疗的不良结果相关。KRASG12C抑制剂的突破性发现显着改善了这种KRAS亚型的预后，尽管疗效仅限于NSCLC患者。KRASG12C抑制剂也能恢复抑制性TME，创造与ICI组合的机会。然而,KRAS抑制剂的一个不可避免的挑战是耐药性。有希望的组合策略，如与SHP2的组合，是一种值得进一步探索的方法，因为它们的免疫调节作用。
