Allele-specific signaling by different KRAS alleles remains poorly understood. The KRAS G12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers.See related commentary by Falcomatà et al., p. 23.This article is highlighted in the In This Issue feature, p. 1.

中文翻译：

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非典型 KRASG12R 突变体在胰腺癌中的 PI3K 信号传导和巨胞饮作用受损。


不同 KRAS 等位基因的等位基因特异性信号传导仍知之甚少。 KRAS G12R 突变在 KRAS 突变发生率最高的癌症中表现出不均匀的患病率：在肺癌和结直肠癌中罕见 (∼1%)，但在胰腺导管腺癌 (PDAC) 中相对常见 (∼20%)，这表明了背景-特定属性。我们评估了 KRASG12R 在功能上是否与更常见的 KRASG12D 或 KRASG12V 突变蛋白 (KRASG12D/V) 不同。我们发现 KRASG12D/V 而不是 KRASG12R 驱动巨胞饮作用，并且 MYC 对于 KRASG12D/V 突变 PDAC 中的巨胞饮作用至关重要，而 KRASG12R 突变体 PDAC 则不然。令人惊讶的是，我们发现由于开关 II 的结构扰动，KRASG12R 与关键效应器 p110α PI3K (PI3Kα) 的相互作用存在缺陷。相反，上调的 KRAS 独立 PI3Kγ 活性能够支持 KRASG12R 突变型 PDAC 中的巨胞饮作用。最后，我们确定与 KRASG12D 突变型 PDAC 相比，KRASG12R 突变型 PDAC 显示出不同的药物敏感性，但仍对 ERK 和自噬的联合抑制有反应。意义：我们确定 KRASG12R 在激活关键效应器 p110α PI3K 方面受到损害。因此，KRASG12R 在驱动巨胞饮作用方面受到损害。然而，PDAC 中 PI3Kγ 的过度表达弥补了这一缺陷，为这种罕见的 KRAS 突变体在胰腺癌而非其他癌症中的流行提供了基础。参见 Falcomatà 等人的相关评论，第 17 页。 23.本文在本期特稿中重点介绍，第 17 页。 1.