Background: Oncogene-driven NSCLC is usually treated with targeted therapies using tyrosine kinase inhibitors (TKIs) to inhibit oncogene downstream signaling pathways, affecting tumor survival and proliferation. EGFR- and KRAS-mutant NSCLCs are the most represented subtypes, and they are treated in clinical practice with oncogene-targeting drugs in the first and second line, respectively. Unfortunately, the development of oncogene-independent resistant clones limits TKI efficacy. Here, we used non-oncogene addiction (NOA) as an innovative therapeutic strategy to target other essential proteins that support changes in tumor phenotype. Specifically, we tested, for the first time, a combination of inhibitors, namely ATR, involved in DNA damage response, and pyruvate dehydrogenase kinases (PDKs), involved in energy metabolism. Methods: Sensitive PC9 and the corresponding EGFR-TKI-resistant PC9/OR, EGFR-mutant H1975, and KRAS-mutant A549 NSCLC cells, were treated with TKIs (osimertinib and selumetinib, respectively). In parallel, cells were exposed to two combination regimens: one using the TKI with an ATR inhibitor and the other one combining the two selected NOA inhibitors (ATR inhibitor, M4344; and PDK inhibitor, DCA). Results: The effect of these two combined approaches, compared to TKI alone, produced similar results in terms of cell proliferation, cell death, and migration. Thus, depending on tumor biology, selecting between the proposed therapeutic strategies will be different, to maximize tumor response. Conclusions: The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted.
背景：驱动基因阳性的非小细胞肺癌通常采用靶向治疗，即使用酪氨酸激酶抑制剂抑制癌基因下游信号通路，从而影响肿瘤的存活与增殖。EGFR突变型和KRAS突变型非小细胞肺癌是最具代表性的亚型，在临床实践中分别采用一线和二线的癌基因靶向药物治疗。然而，非癌基因依赖性耐药克隆的出现限制了酪氨酸激酶抑制剂的疗效。本研究采用非癌基因成瘾性这一创新治疗策略，靶向支持肿瘤表型变化的其他关键蛋白。具体而言，我们首次测试了两种抑制剂的联合应用：一种作用于DNA损伤反应的ATR抑制剂，另一种作用于能量代谢的丙酮酸脱氢酶激酶抑制剂。 方法：分别使用酪氨酸激酶抑制剂（奥希替尼和司美替尼）处理敏感细胞株PC9及其对应的EGFR-TKI耐药株PC9/OR、EGFR突变型H1975细胞和KRAS突变型A549非小细胞肺癌细胞。同时，采用两种联合治疗方案：一种为酪氨酸激酶抑制剂联合ATR抑制剂，另一种为两种选定的非癌基因成瘾性抑制剂联合（ATR抑制剂M4344与PDK抑制剂DCA）。 结果：与单用酪氨酸激酶抑制剂相比，这两种联合方案在细胞增殖、细胞死亡和迁移方面产生了相似的效果。因此，根据肿瘤生物学特性，选择不同的治疗策略将有助于最大化肿瘤反应。 结论：本研究的主要转化意义在于，针对癌基因成瘾性非小细胞肺癌患者，通过开发非癌基因成瘾性药物的创新优化治疗策略，而非联合使用癌基因通路内的靶基因药物，为克服酪氨酸激酶抑制剂耐药提供了新的靶点。
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