在针对 HRAS 突变肿瘤的法呢基转移酶抑制剂 (FTI) 的临床开发中，反应因癌症类型而异。同时发生的突变可能会影响反应。我们的目的是揭示 HRAS 突变肿瘤特有的协同遗传事件，并研究它们对 FTI 敏感性的影响。使用来自 MSK-IMPACT 和丹娜法伯癌症研究所基因组证据肿瘤信息交换数据库的靶向测序数据，我们确定了主要在 HRAS 突变与 KRAS 突变或 NRAS 突变癌症中观察到的突变。与 KRAS 突变 (41.4%) 和 NRAS 突变 (38.4%) 癌症相比，HRAS 突变癌症在 MAPK、PI3K 或 RTK 通路基因中出现联合突变的频率更高 (48.8%) (p<0.05)。 3 类 BRAF、NF1、PTEN 和 PIK3CA 突变在 HRAS 突变谱系中更为普遍。为了研究突变对 FTI 敏感性的影响，将 HrasG13R 转染到“RASless”（Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert）小鼠胚胎成纤维细胞 (MEF) 中，使未转染的 MEF 对替比法尼敏感。在存在或不存在 KrasWT 的情况下，Pten 或 Nf1 缺失和 Pik3caH1047R 转导形式的交换导致 HrasG13R 转染的 MEF 中对替比法尼的耐药性，而 BrafG466E 转导仅在 KrasWT 存在的情况下导致对替比法尼的耐药性。替比法尼和 MEK 抑制联合治疗使细胞在所有情况下都对替比法尼敏感，包括在具有 PI3K 通路突变的 MEF 中。 HRAS 突变肿瘤表现出谱系依赖性 MAPK 或 PI3K 通路改变，从而赋予替比法尼耐药性。 FTI 和 MEK 抑制的联合使用是治疗 HRAS 突变肿瘤的一种有前途的策略。© 2024。作者，获得 Springer Nature Limited 的独家许可。

In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, HrasG13R was transfected into "RASless" (Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3caH1047R transduction led to resistance to tipifarnib in HrasG13R-transfected MEFs in the presence or absence of KrasWT, whereas BrafG466E transduction led to resistance to tipifarnib only in the presence of KrasWT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.