Exploiting KRAS addiction for lung cancer therapy

项目摘要/摘要 利用KRAS成瘾治疗肺癌 有一个巨大的需求尚未得到满足，即开发治疗KRAS突变肺癌的新方法。而25%-30%的 肺腺癌是通过激活KRAS突变而发生的，个别肿瘤可能发展为KRAS 对癌症进展过程漠不关心。众所周知，癌细胞仍在继续发展。 适应以支持肿瘤进展和转移所需的不受控制的生长和生存。 新数据显示，整合素αvβ3在KRAS突变癌细胞上的表达可预测哪些肿瘤 肿瘤生长和锚定非依赖性生长仍然依赖KRAS，这是癌症的一个标志 这是侵袭和转移扩散所必需的。 虽然多种膜受体通过聚集在贴壁细胞中发挥作用，但整合素αvβ3在其 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。预赛 结果证实，非贴壁细胞中整合素α对β3的聚集通过使能 KRAS具有多种驱动抗逆性的功能，包括形成便于 营养吸收和促进有利于氧化还原平衡的基因表达程序。的总体目标 该提案旨在定义α与β3介导的KRAS集群如何促进推动KRAS的生存优势 成瘾并在体内促进肺癌的发生、发展和转移。了解 这一途径的关键分子机制将促进新疗法的设计，以开发独特的 KRAS突变癌症的脆弱性。 该多PI R01的具体目的是为了了解细胞和分子生物学作用 αvβ3作为KRAS成瘾的调节器(目标1-由切列什博士领导)，并了解它与癌症的关系 致癌基因Kras基因工程小鼠肺癌模型的建立和进展 (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- 用于癌症治疗的上瘾细胞(目标3--合作努力)。 目的1：建立α-v-β-3体外调节KRAS功能的分子基础 目的2：确定α和β3在体内对Kras驱动的非小细胞肺癌的影响 目标3：利用KRAS成瘾来加强癌症治疗

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