Scholarlink

<p>Mutations in <i>KRAS</i> are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with about 50% of patients presenting with <i>KRAS</i><sup><i>G12D</i></sup> mutations. Small molecule inhibitors targeting KRAS<sup>G12D</sup> suppress PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained efficacy of KRAS<sup>G12D</sup> inhibition and mechanisms of resistance to KRAS<sup>G12D</sup> suppression remain to be elucidated. Here, integrated spatial transcriptomics, single-cell RNA sequencing, and CODEX-based spatial proteomics analyses of PDAC mouse models uncover that while KRAS<sup>G12D</sup> inhibition by MRTX1133 initially increases CD11c<sup>+</sup> cells and T cell infiltration proximal to cancer cells, long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8. CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself or in combination with αCTLA-4 immunotherapy overcomes resistance to KRAS<sup>G12D</sup> inhibition. We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RAS<sup>G12D</sup>(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

CDK8 remodels the tumor microenvironment and promotes resistance to KRASG12D inhibitors and daraxonrasib in PDAC

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月11日

查看全文
  • Kathleen M McAndrews,
  • Krishnan K Mahadevan,
  • Bingrui Li,
  • Anaïs M Comptdaer,
  • Amari M Sockwell,
  • Sami J Morse,
  • Patience J Kelly,
  • Sarah I Patel,
  • Michelle L Kirtley,
  • Barbara A Moreno Diaz,
  • Hengyu Lyu,
  • David H Peng,
  • Sima Khazaei,
  • Aislyn Schalck,
  • Xunian Zhou,
  • Hikaru Sugimoto,
  • Aaron A Bickert,
  • Lakshmi Kavitha Sthanam,
  • Meagan R Taylor,
  • Shreyasee V Kumbhar,
  • Kent A Arian,
  • Yasaman Barekatain,
  • Francesca Paradiso,
  • Paola A Guerrero,
  • Vincent Bernard,
  • Navid Sobhani,
  • Alondra N Camacho-Acevedo,
  • Kiara E Bornes,
  • Phuong Thao Tran,
  • Anirban Maitra,
  • Timothy P Heffernan,
  • Raghu Kalluri

摘要

Mutations in KRAS are a dominant driver of pancreatic ductal adenocarcinoma (PDAC), with about 50% of patients presenting with KRASG12D mutations. Small molecule inhibitors targeting KRASG12D suppress PDAC; however, the contribution of the tumor microenvironment (TME) to the sustained efficacy of KRASG12D inhibition and mechanisms of resistance to KRASG12D suppression remain to be elucidated. Here, integrated spatial transcriptomics, single-cell RNA sequencing, and CODEX-based spatial proteomics analyses of PDAC mouse models uncover that while KRASG12D inhibition by MRTX1133 initially increases CD11c+ cells and T cell infiltration proximal to cancer cells, long-term treatment results in reversal of the immune responses leading to resistance promoted by multiprotein mediator complex associated kinase CDK8. CDK8 imparts this resistance via induction of CXCL2 chemokine secretion, inhibition of FAS expression, and remodeling of the TME to promote immune evasion. Targeting CDK8 by itself or in combination with αCTLA-4 immunotherapy overcomes resistance to KRASG12D inhibition. We also provide evidence of CDK8 upregulation in PDX tumors resistant to inhibitors selective for RAS(ON) and RASG12D(ON): daraxonrasib and zoldonrasib, respectively, highlighting a common KRAS vulnerability node for TME resistance.