077 Isoform-specific aPKC maintains Hedgehog signaling in the absence of primary cilia

Abstract

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) and medulloblastoma accumulate mutations in the Alström and Usher syndrome genes. Loss of Alström and Usher syndrome gene expression, which are common underlying causes of deafness and blindness, suppresses ciliogenesis and HH signaling. Loss of primary cilia also enhances atypical protein kinase C iota/lambda (aPKC) expression, a GLI1 kinase necessary for advanced BCC growth. We show that aPKC expression is inversely correlated with primary ciliogenesis and that superficial BCCs display less primary cilia and higher aPKC expression, with the opposite true in nodular BCC subtypes. Surprisingly, a constitutively active isoform of aPKC drives HH pathway activity but not full-length protein. 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. Our results suggest tumors enhance isoform-specific expression of aPKC to prevent mutation-induced cessation of tumor growth and that aPKC may serve as a biomarker for SMO inhibitor sensitivity.