Preclinical studies of KRAS and EGFR mutations in lung cancer PDXs

项目总结/摘要 本申请是为了响应被标识为NOT-CA的特别利益通知（NOSI）而提交的- 22-039.肺癌是所有美国人癌症发病率和死亡率的主要原因， 在有色人种社区中的比例非常高。例如，与白人相比，非洲裔美国人和 拉丁美洲人的早期肺癌诊断率分别为18%和16%。5年生存 非洲裔美国人和拉丁美洲人的死亡率也比白色患者低21%和16%。然而，发病率和 美国少数民族的死亡率与他们的吸烟率密切相关。在非裔美国人和 一些亚洲/太平洋岛民群体，如夏威夷人和萨摩亚人，肺癌是癌症的首要原因 mortality.非裔美国男性肺癌的发病率和死亡率 分别比白色男性高出15%和18%。即使在拉丁美洲人中，吸烟率最低的种族群体也是如此。 在美国，肺癌仍然是男性癌症死亡的第一原因。EGFR和KRAS最常见 肺肿瘤中的突变，并与种族，吸烟和遗传祖先密切相关。KRAS是 通常在白人和非裔美国人、男性和吸烟者/前吸烟者中诊断。亚洲人和 另一方面，拉丁美洲人的KRAS突变频率明显较低，但富含 EGFR突变。亚洲和拉丁裔患者的EGFR突变在从不吸烟的女性中普遍存在。直到 最近，大多数肺癌的靶向治疗都是针对EGFR突变型肿瘤开发的，而KRAS 被认为是“不可抵抗的”然而，在过去的12个月中，随着FDA批准 sotorasib，一种增加携带肿瘤的总体缓解率和无进展生存期的分子， KRAS G12 C突变。尽管有这些重要的进展，但很大一部分患者要么缺乏 对EGFR和KRAS靶向治疗有反应或产生耐药性。在这篇补充文章中，我们利用 我们的少数民族PDX（MPDX）中心的资源，以调查与响应相关的机制， 在来自白色和少数民族患者的模型中，我们的具体目标如下： 目标1。为了确定在存在或不存在双重抑制剂的情况下，sotorasib的直接KRAS G12 C抑制活性， Sapanisertib和telaglenastat（CB 839）对KRAS G12 C突变体糖酵解和谷氨酰胺分解的抑制 具有临床相关共改变的PDX（p53/Keap 1）。目标二。进行可行性研究， 与亚洲和白色患者肺PDX中EGFR抑制剂耐药相关的生物标志物。这 该项目将增加我们对午餐癌靶向治疗反应的理解，并作为一个 未来在白色和少数民族患者中进行精准医疗临床试验的跳板。

PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 22-039. Lung cancer is the leading cause of cancer incidence and mortality in all Americans but disproportionally high in communities of color. Compared to Whites, for example, African Americans and Latinos are 18% and 16% less likely to have an early lung cancer diagnosis, respectively. The 5-year survival of African Americans and Latinos is also 21% and 16% lower than White patients. However, the incidence and mortality rates in US minority populations are closely linked to their smoking rates. In African American and some Asian/Pacific Islander groups such as Hawaiian and Samoan, lung cancer is the top cause of cancer mortality. Lung cancer disproportionally affects African American men, who have incidence and mortality rates of 15% and 18% higher than White men. Even in Latinos, the ethnic group with the lowest smoking rates in the nation, lung cancer remains the first cause of cancer mortality in men. EGFR and KRAS are the most common mutations in lung tumors and are strongly associated with race, smoking, and genetic ancestry. KRAS is commonly diagnosed in Whites and African Americans, in men and smokers/former smokers. Asians and Latinos, on the other hand, have a significantly lower frequency of KRAS mutations but are enriched with mutations in EGFR. EGFR mutations in Asian and Latino patients are prevalent in never smoker women. Until recently, most of the targeted therapies for lung cancer were developed for EGFR mutant tumors, while KRAS was considered “undruggable.” This, however, changed in the last 12 months with the FDA approval of sotorasib, a molecule that increases overall response rate and progression-free survival in tumors carrying the KRAS G12C mutation. Despite these important advances, a significant fraction of patients either lack response or develop resistance to EGFR and KRAS targeted therapies. In this supplement, we are leveraging the resources of our minority PDX (MPDX) center to investigate mechanisms associated with response to inhibitors for KRAS and EGFR in models from White and minority patients. Our Specific Aims are as follows: Aim 1. To determine the activity of direct KRAS G12C inhibition of sotorasib in the presence or absence of dual inhibition of glycolysis and glutaminolysis with sapanisertib and telaglenastat (CB839) in KRAS G12C mutant PDXs with clinically relevant co-alterations (p53/Keap1). Aim 2. To carry out a feasibility study for identifying biomarkers associated with EGFR inhibitor resistance in lung PDXs from Asian and White patients. This project will increase our understanding of responses to targeted therapies for lunch cancer and serve as a springboard for future clinical trials on precision medicine in white and minority patients.