Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway–dependent cancers, the scope of mechanisms enabling resistance to SMO inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to SMO inhibitors and maintains a “persister” state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.

Significance: Using a transposon screen and clinical datasets, we identified mutations in ciliogenesis genes as a new class of resistance to SMO inhibitors. Mechanistically, cilia-mutant tumors can either grow slowly in a “persister” state or evolve and progress rapidly in an “aggressive” state. Cancer Discov; 7(12); 1436–49. ©2017 AACR.

See related commentary by Goranci-Buzhala et al., p. 1374.

This article is highlighted in the In This Issue feature, p. 1355

耐药性对靶向癌症治疗提出了巨大挑战。在Hedgehog途径依赖性癌症中，对SMO抑制剂具有抗药性的机制范围尚不清楚。在这里，我们在髓母细胞瘤中进行了转座子诱变筛选，并确定了多种耐药模式。出人意料的是，纤毛发生基因中的突变代表耐药性的常见原因，并且患者数据集表明纤毛损失构成了耐药性的临床相关类别。传统上，原发纤毛被认为能够致癌的刺猬信号。矛盾的是，我们发现纤毛损失保护了肿瘤细胞免受SMO抑制剂的敏感性，并维持了“刺猬”状态，这取决于刺猬程序的持续低输出。持久性细胞可以作为肿瘤进一步发展的储存库，因为其他改变与纤毛损失协同作用，从而产生侵袭性复发性肿瘤。在一起，我们的发现揭示了耐药性的模式，并为纤毛在肿瘤进化和耐药性中的作用提供了机械方面的见解。

意义：使用转座子筛选和临床数据集，我们将纤毛生成基因中的突变鉴定为对SMO抑制剂的新型抗药性。从机理上讲，纤毛突变型肿瘤可以在“ persister”状态下缓慢生长，或在“ aggressive”状态下快速生长和进展。巨蟹座Discov; 7（12）；1436–49。©2017 AACR。

参见Goranci-Buzhala等人的相关评论，第1页。1374。

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