KRAS mutation is a key driver of pancreatic cancer and PI3K pathway activity is an additional requirement for Kras-induced tumorigenesis. Clinical trials of PI3K pathway inhibitors in pancreatic cancer have shown limited responses. Understanding the molecular basis for this lack of efficacy may direct future treatment strategies with emerging PI3K inhibitors. We sought new therapeutic approaches that synergize with PI3K inhibitors through pooled CRISPR modifier genetic screening and a drug combination screen. ERBB family receptor tyrosine kinase signaling and mTOR signaling were key modifiers of sensitivity to alpelisib and pictilisib. Inhibition of the ERBB family or mTOR was synergistic with PI3K inhibition in spheroid, stromal cocultures. Near-complete loss of ribosomal S6 phosphorylation was associated with synergy. Genetic alterations in the ERBB–PI3K signaling axis were associated with decreased survival of patients with pancreatic cancer. Suppression of the PI3K/mTOR axis is potentiated by dual PI3K and ERBB family or mTOR inhibition. Surprisingly, despite the presence of oncogenic KRAS, thought to bestow independence from receptor tyrosine kinase signaling, inhibition of the ERBB family blocks downstream pathway activation and synergizes with PI3K inhibitors. Further exploration of these therapeutic combinations is warranted for the treatment of pancreatic cancer.

中文翻译：

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基因组规模的 CRISPR 筛选将 ERBB 和 mTOR 信号网络识别为胰腺癌中对 PI3K 抑制反应的关键决定因素

KRAS 突变是胰腺癌的关键驱动因素，而 PI3K 通路活性是 Kras 诱导的肿瘤发生的额外要求。PI3K 通路抑制剂在胰腺癌中的临床试验显示反应有限。了解这种缺乏疗效的分子基础可能会指导未来使用新兴 PI3K 抑制剂的治疗策略。我们通过合并的 CRISPR 修饰基因筛选和药物组合筛选，寻求与 PI3K 抑制剂协同作用的新治疗方法。ERBB 家族受体酪氨酸激酶信号和 mTOR 信号是对 alpelisib 和 pictilisib 敏感性的关键调节剂。ERBB 家族或 mTOR 的抑制与球体、基质共培养中的 PI3K 抑制具有协同作用。核糖体 S6 磷酸化的近乎完全丧失与协同作用有关。ERBB-PI3K 信号轴的遗传改变与胰腺癌患者的存活率降低有关。PI3K/mTOR 轴的抑制由双重 PI3K 和 ERBB 家族或 mTOR 抑制增强。令人惊讶的是，尽管存在致癌 KRAS，被认为独立于受体酪氨酸激酶信号传导，但抑制 ERBB 家族会阻止下游途径激活并与 PI3K 抑制剂协同作用。需要进一步探索这些治疗组合以治疗胰腺癌。被认为独立于受体酪氨酸激酶信号传导，ERBB 家族的抑制会阻止下游途径的激活并与 PI3K 抑制剂协同作用。需要进一步探索这些治疗组合以治疗胰腺癌。被认为独立于受体酪氨酸激酶信号传导，ERBB 家族的抑制会阻止下游途径的激活并与 PI3K 抑制剂协同作用。需要进一步探索这些治疗组合以治疗胰腺癌。