Exploiting KRAS addiction for lung cancer therapy

项目概要/摘要 利用KRAS成瘾治疗肺癌 对于开发用于KRAS突变型肺癌的新方法存在巨大的未满足的需求。而25-30%的 肺腺癌是由于激活KRAS突变而发生的，个体肿瘤可能发展为KRAS 对癌症发展过程漠不关心。众所周知，癌细胞会继续发展， 适应以支持肿瘤进展和转移所需的不受控制的生长和存活。 新的数据表明，KRAS突变癌细胞上整合素αvβ3的表达预测了哪些肿瘤 肿瘤生长以及锚定非依赖性生长（癌症的标志）仍然依赖于KRAS 是侵袭和转移扩散所必需的。 虽然多种膜受体通过聚集在粘附细胞中起作用，但整合素αvβ3在其粘附细胞中是独特的。 在没有细胞外基质锚定的情况下聚集和驱动信号通路的能力。初步 结果表明，整合素αvβ3在非贴壁细胞中的聚集通过使KRAS成瘾性增加而引起KRAS成瘾。 KRAS的多种功能，包括形成大胞饮体， 营养吸收和促进有利于氧化还原平衡的基因表达程序。的总目标 这一提议旨在定义αvβ3介导的KRAS聚集如何促进生存优势， 成瘾性，并有助于肺癌的启动，发展和体内转移。了解 对这一途径至关重要的分子机制将促进新疗法的设计， KRAS突变癌症的脆弱性。 本Multi-PI R 01的特定目的旨在了解细胞和分子生物学作用， αvβ3作为KRAS成瘾的调节剂（目标1 -由Cheresh博士领导），并了解这与癌症的关系 使用由致癌Kras驱动的肺癌的基因工程小鼠模型的起始和进展 (Aim 2 -由Onaitis博士领导）。这些发现将使针对KRAS的新战略的逻辑设计成为可能- 成瘾细胞用于癌症治疗（目标3 -合作努力）。 目的1：建立αvβ3体外调控KRAS功能的分子基础 目的2：确定αvβ3对体内Kras驱动的NSCLC的影响 目的3：利用KRAS成瘾来增强癌症治疗

Project Summary/Abstract Exploiting KRAS addiction for lung cancer therapy There is a great unmet need to develop new approaches for KRAS mutant lung cancers. While 25-30% of lung adenocarcinomas arise by virtue of activating KRAS mutations, individual tumors may develop KRAS indifference over the course of cancer progression. It is well-appreciated that cancer cells continue to develop adaptations to support the uncontrolled growth and survival required for tumor progression and metastasis. New data shows that the expression of integrin αvβ3 on KRAS mutant cancer cells predicts which tumors remain dependent on KRAS for tumor growth as well as anchorage-independent growth, a hallmark of cancer that is required for invasion and metastatic spread. While a variety of membrane receptors function by clustering in adherent cells, integrin αvβ3 is unique in its ability to cluster and drive signaling pathways in the absence of extracellular matrix anchoring. The Preliminary Results establish that integrin αvβ3 clustering in non-adherent cells gives rise to KRAS addiction by enabling multiple functions of KRAS that drive stress tolerance, including formation of macropinosomes that facilitate nutrient uptake and promotion of a gene expression program that favors redox balance. The overall goals of this proposal are to define how αvβ3-mediated KRAS clustering promotes survival advantages that drive KRAS addiction and contribute to lung cancer initiation, progression, and metastasis in vivo. Understanding the molecular mechanisms critical for this pathway will foster the design of new therapies to exploit the unique vulnerabilities of KRAS mutant cancers. The Specific Aims of this Multi-PI R01 are designed to understand the cell and molecular biological role for αvβ3 as a regulator of KRAS addiction (Aim 1 – led by Dr. Cheresh) and to learn how this relates to cancer initiation and progression using genetically-engineered mouse models of lung cancer driven by oncogenic Kras (Aim 2 – led by Dr. Onaitis). These findings will enable the logical design of new strategies to target KRAS- addicted cells for cancer therapy (Aim 3 – a collaborative effort). Aim 1: Establish the molecular basis for αvβ3 regulation of KRAS functions in vitro Aim 2: Define the impact of αvβ3 on Kras-driven NSCLC in vivo Aim 3: Exploit KRAS addiction to enhance cancer therapy