%0 Journal Article %A Tuyen T. L. Nguyen %A Ung Seop Jeon %A Vama Jhumkhawala %A Kevin C. Tan %A Vinay Kumar %A Whitney E. England %A Linda T. Doan %A Robert C. Spitale %A Scott X. Atwood %T aPKC drives cilia-independent Hedgehog signaling to maintain basal cell carcinoma growth %D 2020 %R 10.1101/2020.06.08.137216 %J bioRxiv %P 2020.06.08.137216 %X Primary cilia loss is a common feature of advanced cancers. While primary cilia are necessary to initiate Hedgehog (HH)-driven cancers, how HH pathway activity is maintained in advanced cancers devoid of primary cilia is unclear. Here, we find that HH-driven basal cell carcinoma (BCC) accumulate mutations in the Alström and Usher syndrome genes in advanced and SMO inhibitorresistant tumors. Loss of Alström and Usher syndrome gene expression, which are common underlying causes of deafness and blindness, suppresses ciliogenesis and HH signaling. Atypical protein kinase C iota/lambda (aPKC) is a GLI1 kinase with higher expression in advanced BCCs and we show that a constitutively active isoform drives HH pathway activity and mutually antagonizes primary cilia. Overexpression of the constitutively active aPKC variant can maintain HH pathway activity in the absence of primary cilia and can drive resistance to the SMO antagonist vismodegib regardless of cilia status. Finally, superficial BCCs display less primary cilia and higher aPKC expression, which is inversely correlated in nodular BCC subtypes. Our results suggest aPKC may serve as a biomarker for SMO inhibitor sensitivity and a target for clinical application.Competing Interest StatementThe authors have declared no competing interest. %U https://www.biorxiv.org/content/biorxiv/early/2020/06/09/2020.06.08.137216.full.pdf