Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
Vanderbilt Ingram Cancer Center and Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN.
JCO Precis Oncol. 2022 Aug;6:e2200088. doi: 10.1200/PO.22.00088.
The identification of novel oncogenic driver alterations and novel mechanisms of acquired resistance (AR) is the key for further development of personalized therapy. The current study investigates the potential role of amplification as a primary driver of tumorigenesis and of amplifications as mediators of AR to ALK and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).
Models of ectopic expression were established and characterized for YES1 and YAP1 in human bronchial epithelial cells and fusion-positive (ALK+) and -mutant lung adenocarcinoma cell lines. MSK-IMPACT data for all lung adenocarcinoma cases and for ALK and EGFR TKI AR cases were surveyed for and amplification.
We report response to SRC family kinase (SFK) inhibition in a patient whose lung cancer exhibited amplification, without any well-established primary driver alteration, suggesting that amplification can also function as a primary oncogenic driver. To investigate the possibility of as a primary driver in tumorigenesis, we established preclinical models of YES1 overexpression using human bronchial epithelial cells and normal human breast epithelial cells. We showed that YES1 overexpression conferred sensitivity to SFK TKIs and promoted EGF-independent growth in a YAP1-dependent manner. Analysis of clinical genomic sequencing data from cases of AR to EGFR and ALK inhibitors revealed acquired amplification of in four cases. -mutant and fusion-positive cells overexpressing YES1 or YAP1 were resistant to EGFR and ALK TKIs, respectively, but were sensitive to dual inhibition of the primary driver and YES1.
Our results demonstrate the therapeutic potential of SFK inhibition in primary tumorigenesis and AR driven by YES1/YAP1 signaling.
鉴定新的致癌驱动改变和获得性耐药（AR）的新机制是进一步开发个体化治疗的关键。本研究探讨了扩增作为肿瘤发生主要驱动因素的潜在作用，以及 扩增作为 ALK 和表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）AR 的介质的作用。
在人支气管上皮细胞和融合阳性（ALK+）和 -突变肺腺癌细胞系中建立并表征了 YES1 和 YAP1 的异位表达模型。调查了所有肺腺癌病例和 ALK 和 EGFR TKI AR 病例的 MSK-IMPACT 数据中 是否有 扩增。
我们报告了一位肺癌患者对 SRC 家族激酶（SFK）抑制剂有反应，而没有任何明确的主要驱动改变，这表明 扩增也可以作为一种主要的致癌驱动因素。为了研究 是否可以作为肿瘤发生的主要驱动因素，我们使用人支气管上皮细胞和正常人类乳腺上皮细胞建立了 YES1 过表达的临床前模型。我们表明，YES1 过表达赋予了 SFK TKI 的敏感性，并以 YAP1 依赖的方式促进了 EGF 非依赖性生长。对 EGFR 和 ALK 抑制剂 AR 病例的临床基因组测序数据进行分析显示，有 4 例发生了 获得性扩增。过表达 YES1 或 YAP1 的 -突变和 融合阳性细胞对 EGFR 和 ALK TKI 耐药，但对主要驱动和 YES1 的双重抑制敏感。
我们的结果表明，SFK 抑制在 YES1/YAP1 信号驱动的原发性肿瘤发生和 AR 中具有治疗潜力。
