Kinase inhibitor resistance constitutes a major unresolved clinical challenge in cancer. Furthermore, the role of serine/threonine phosphatase deregulation as a potential cause for resistance to kinase inhibitors has not been thoroughly addressed. We characterize protein phosphatase 2A (PP2A) activity as a global determinant of KRAS-mutant lung cancer cell resistance across a library of >200 kinase inhibitors. The results show that PP2A activity modulation alters cancer cell sensitivities to a large number of kinase inhibitors. Specifically, PP2A inhibition ablated mitogen-activated protein kinase kinase (MEK) inhibitor response through the collateral activation of AKT/mammalian target of rapamycin (mTOR) signaling. Combination of mTOR and MEK inhibitors induced cytotoxicity in PP2A-inhibited cells, but even this drug combination could not abrogate MYC up-regulation in PP2A-inhibited cells. Treatment with an orally bioavailable small-molecule activator of PP2A DT-061, in combination with the MEK inhibitor AZD6244, resulted in suppression of both p-AKT and MYC, as well as tumor regression in two KRAS-driven lung cancer mouse models. DT-061 therapy also abrogated MYC-driven tumorigenesis. These data demonstrate that PP2A deregulation drives MEK inhibitor resistance in KRAS-mutant cells. These results emphasize the need for better understanding of phosphatases as key modulators of cancer therapy responses.

激酶抑制剂耐药性是癌症中尚未解决的主要临床挑战。此外，丝氨酸/苏氨酸磷酸酶失调作为激酶抑制剂抗性的潜在原因的作用尚未得到彻底解决。我们将蛋白磷酸酶 2A (PP2A) 活性表征为跨 >200 种激酶抑制剂库的 KRAS 突变肺癌细胞耐药性的全局决定因素。结果表明，PP2A 活性调节改变了癌细胞对大量激酶抑制剂的敏感性。具体而言，PP2A 抑制通过 AKT/哺乳动物雷帕霉素靶标 (mTOR) 信号传导的附带激活来消除丝裂原活化蛋白激酶激酶 (MEK) 抑制剂反应。mTOR 和 MEK 抑制剂的组合在 PP2A 抑制的细胞中诱导细胞毒性，但即使这种药物组合也不能消除 PP2A 抑制细胞中的 MYC 上调。用 PP2A DT-061 的口服生物可利用小分子激活剂与 MEK 抑制剂 AZD6244 联合治疗，可抑制 p-AKT 和 MYC，以及两种 KRAS 驱动的肺癌小鼠模型的肿瘤消退。DT-061 疗法还消除了 MYC 驱动的肿瘤发生。这些数据表明 PP2A 失调驱动 KRAS 突变细胞中的 MEK 抑制剂抗性。这些结果强调需要更好地理解磷酸酶作为癌症治疗反应的关键调节剂。以及两种 KRAS 驱动的肺癌小鼠模型中的肿瘤消退。DT-061 疗法还消除了 MYC 驱动的肿瘤发生。这些数据表明 PP2A 失调驱动 KRAS 突变细胞中的 MEK 抑制剂抗性。这些结果强调需要更好地理解磷酸酶作为癌症治疗反应的关键调节剂。以及两种 KRAS 驱动的肺癌小鼠模型中的肿瘤消退。DT-061 疗法还消除了 MYC 驱动的肿瘤发生。这些数据表明 PP2A 失调驱动 KRAS 突变细胞中的 MEK 抑制剂抗性。这些结果强调需要更好地理解磷酸酶作为癌症治疗反应的关键调节剂。