08 2015

Cancer Cell and Journal of Investigative Dermatology published our papers describing how the majority of basal cell carcinomas aquire drug resistance and their genetic diversity Scott Atwood

Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. These genetic alterations suggest that SMO functions similarly to other class A GPCRs despite less than 10% sequence identity. In the presence of a SMO inhibitor, tumor cells containing both classes of SMO mutants effectively compete against cells containing wild type SMO. Finally, we show that both classes of SMO variants respond to aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.

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Genomic analysis by our group and others have revealed that basal cell carcinomas (BCCs) carry a high frequency of non-silent mutations, yet how these mutations confer selective tumor growth without deleterious effects remains poorly understood. Here, we find that Smoothened (SMO) mutations are frequently found across many cancers with drug-resistant BCCs bearing the highest rate of recurrent mutations at 66%. We identify 28 mutations in SMO that were either recurrent, overlap with the COSMIC database, or were region-specific and interrogated their ability to promote HH signaling. We find that each mutation exerts either neutral or negative effects on HH signaling with a subset of mutations abolishing SMO function. This was surprising as nearly half of the residues lie in the pivot regions or the ligand binding pocket of SMO, which control protein activity and binding of SMO inhibitors, respectively. Our data supports a model where tumors are permissive to genetic mutations, generating many genetically diverse clones that compete as a way to grow. As we expand our use of high-throughput sequencing of tumors for personalized medicine, our results present a cautionary tale to functionally validate any mutation before concluding their ability to exert oncogenic effects.

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