Abstract:
: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. 1374This article is highlighted in the In This Issue feature, p. 1355.
journal_name
Cancer Discovjournal_title
Cancer discoveryauthors
Zhao X,Pak E,Ornell KJ,Pazyra-Murphy MF,MacKenzie EL,Chadwick EJ,Ponomaryov T,Kelleher JF,Segal RAdoi
10.1158/2159-8290.CD-17-0281subject
Has Abstractpub_date
2017-12-01 00:00:00pages
1436-1449issue
12eissn
2159-8274issn
2159-8290pii
2159-8290.CD-17-0281journal_volume
7pub_type
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