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Vismodegib Resistance in Basal Cell Carcinoma: Not a Smooth Fit

Todd W. Ridky1 and George Cotsarelis1,* 1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, BRB 1053, 421 Curie Boulevard, Philadelphia, PA 19104, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ccell.2015.02.009

In this issue of Cancer Cell, two complementary papers by Atwood and colleagues and Sharpe and colleagues show that basal cell carcinomas resistant to the Smoothened (SMO) inhibitor vismodegib frequently harbor SMO mutations that limit drug binding, with mutations at some sites also increasing basal SMO activity.

Basal cell carcinoma (BCC) of the skin is target, Smoothened (SMO), was subse- to mutations downstream of SMO at the the most common human cancer in lightly quently identified in 2000 (Cooper et al., level of Gli2 or SUFU (a Gli regulator). pigmented individuals. Mutations acti- 1998; Incardona et al., 1998; Taipale By aligning the mutations with a vating the Hedgehog (HH) signaling et al., 2000). That initial work defining recently solved crystal structure of the pathway drive BCC. Secreted HH exerts the SMO-cyclopamine interaction also SMO transmembrane domain, the au- its effects through binding to Patched included the observation that some thors were able to separate the resis- (PTCH), a 12-pass membrane bound re- SMO point mutants driving BCCs not tance-associated mutations into two ceptor, which relieves PTCH inhibitory only increase basal SMO activity, but groups: (1) mutations within or immedi- activity on the downstream heptahelical simultaneously confer cyclopamine resis- ately adjacent to the ligand/drug binding transmembrane protein Smoothened tance. The elegant and comprehensive pocket and (2) mutations at more distant (SMO). How PTCH actually inhibits SMO work presented by Atwood et al. (2015) sites. Using HH pathway reporter con- is not clear, but SMO activation leads to and Sharpe et al. (2015) in this issue of structs in cell lines engineered to express downstream activation of Gli transcription Cancer Cell uses cutting edge technol- mutant SMO proteins, both groups factors that ultimately drive HH target ogy and a large collection of tumor demonstrate that the resistance-associ- gene expression. Several human malig- samples to pinpoint exact mutations in ated mutations confer vismodegib resis- nancies including medulloblastoma (MB) SMO that confer resistance to vismode- tance. Interestingly, the mutations outside and BCC are driven by mutations in gib, the cyclopamine analog used to treat of the ligand binding pocket also increase one or more HH pathway genes, most HH driven tumors. the basal activity of SMO, even in the commonly PTCH1. Germline mutations Because most BCCs are driven by absence of the inhibitor. These mutations in PTCH1 cause Gorlin’s syndrome, which PTCH mutations, most tumors initially include the W535L mutation, a bona fide is associated with developmental abnor- respond to vismodegib. However, at least oncodriver highlighted in the seminal malities and tumor susceptibility that in- 20% develop resistance. The two papers work that established SMO as the cyclop- cludes BCC and MB. HH signaling is by Atwood et al. (2015) and Sharpe et al. amine target. Tumors harboring this mu- critical during embryologic development (2015) show that BCC resistance to the tation at the outset should not respond but has only limited roles in adult tissues, SMO inhibitor is frequently the result of to vismodegib. In contrast, the binding making it an excellent target for cancer mutations in SMO, similar to resistance pocket mutations have little effect on therapeutics. mechanisms for MB (Yauch et al., 2009). basal SMO activity and are likely not suffi- The development of drugs targeting Both groups sequenced DNA from cient oncodrivers on their own, because the HH pathway began in 1957 when BCCs arising in three settings: (1) sponta- most are still inhibited by PTCH1. Idaho farmers noted that many of their neously in the general population, (2) In addition to cell-based functional newborn sheep were born with severe Gorlin’s syndrome patients, and (3) recur- studies demonstrating vismodegib resis- developmental defects, including a single rent/resistant tumors in patients treated tance and computer modeling predicting cyclopic eye. Curiously, the pregnant with vismodegib. Findings from the two altered binding affinity, Sharpe et al. mothers had no obvious symptoms. An studies are quite similar, showing that (2015) used physical biochemisty ap- 11-year Food and Drug Administration 15%–33% of untreated BCCs harbor proaches with 3H-labeled vismodegib to investigation eventually identified the SMO mutations. This increases to 69%– demonstrate that SMO mutations inside veratrum alkaloid cyclopamine, which 77% in resistant tumors. Resistant tumors and outside the ligand binding pocket was present in the California corn lily without SMO mutations still maintain HH both compromise drug binding. They plant growing in the fields grazed by pathway activation, as evidenced by a also demonstrate that vismodegib resis- sheep, as the causative agent. Thirty high level HH target gene (Gli) expression tant mutations confer cross-resistance years later, a pair of papers using avian and relatively unchanged tumor histology. to other small molecule SMO inhibitors, systems determined that cyclopamine In many of these resistant cases without suggesting that combinations of SMO in- inhibits HH signaling, and the molecular SMO mutations, resistance is likely due hibitors from the vismodegib class will

Cancer Cell 27, March 9, 2015 ª2015 Elsevier Inc. 315 Cancer Cell Previews

likely not provide additional trioxide, which promotes Gli therapeutic benefit. HH protein degradation and also vismodegib As predicted by Peter inhibits HH activity driven by Nowell’s classic evolutionary an inhibitor-resistant SMO model of tumor development mutation. Because BCC (Nowell, 1976), the hetero- itraconazole tumors have demonstrated geneity of mutations within SMO several mechanisms of different cells within a tumor PTCH bypassing SMO inhibitors SUFU protects against the demise ι/λ that maintain HH signaling, PSI aPKC of the tumor by specifically Gli perhaps the optimal thera- targeted therapies. The inevi- Arsenic trioxide peutic approach will be to table conclusion from this treat patients with multiple work, as also seen with the inhibitors from the outset, Gli remarkable new therapies rather than sequentially as for melanoma, is that, while resistant clones emerge. targeted agents can produce spectacular initial responses, REFERENCES resistance develops as minor clones expand in the pres- Atwood, S.X., Li, M., Lee, A., Tang, ence of drug. Both groups J.Y., and Oro, A.E. (2013). Nature Figure 1. HH Signaling Pathway 494, 484–488. conclude that, unlike many BCC is driven by activation of the HH pathway. Normally, Patched signaling in- other human malignancies, hibits Smoothened, which prevents Smoothened from activating Gli transcrip- Atwood, S.X., Sarin, K.Y., Whitson, tion factors that transcribe HH target genes. Gli is also inhibited by Supressor of which are capable of R.J., Li, J.R., Kim, G., Rezaee, M., fused (SUFU) and activated by aPKC-i/l. During development, and in a few Ally, M.S., Kim, J., Yao, C., Chang, engaging other mitogenic adult tissues, HH binds to Patched, releasing its inhibitory activity on SMO A.L.S., et al. (2015). Cancer Cell pathways to circumvent tar- and thereby activating the pathway. BCC is driven most commonly by inactivat- 27, this issue, 342–353. PTCH geting inhibitors, BCC ap- ing mutations in , although activating mutations in SMO or Gli can also serve as oncodrivers. Tumor resistance to vismodegib usually results from Cooper, M.K., Porter, J.A., Young, pears dependent on the SMO mutations that prevent drug binding. Targeting the pathway downstream K.E., and Beachy, P.A. (1998). Sci- HH pathway. Therefore, over- may therefore be a useful therapeutic strategy. Red, elements that normally ence 280, 1603–1607. coming vismodegib resis- suppress HH signaling; green, elements that activate the pathway; yellow, phar- macologic agents that may be useful for primary or vismodegib resistant BCC. Incardona, J.P., Gaffield, W., Kapur, tance will require combina- R.P., and Roelink, H. (1998). Devel- tion therapy with agents that opment 125, 3553–3562. inhibit SMO through different mecha- downstream of SMO would be predicted Kim, J., Aftab, B.T., Tang, J.Y., Kim, D., Lee, nisms or that target the HH pathway at to lead to resistance to any SMO-targeted A.H., Rezaee, M., Kim, J., Chen, B., King, points downstream of SMO. Potential inhibitor, so an ideal therapeutic approach E.M., Borodovsky, A., et al. (2013). Cancer Cell 23 SMO-targeting agents with efficacy may include a drug combination that also , 23–34. against SMO resistant mutants include targets Gli. In that regard, Atwood et al. Nowell, P.C. (1976). Science 194, 23–28. substituted bis-amides (which have struc- (2015) present data using an atypical pro- tural similarity to vismodegib) and the tein kinase C i/l (aPKC-i/l) inhibitor that Sharpe, H.J., Pau, G., Dijkgraaf, G.J., Basset- FDA-approved antifungal agent itracona- inhibits Gli activation and retains efficacy Seguin, N., Modrusan, Z., Januario, T., Tsui, V., Durham, A.B., Dlugosz, A.A., Haverty, M.P., zole, which targets SMO at a site distinct in the presence of the SMO mutations (At- et al. (2015). Cancer Cell 27, this issue, 327–341. from vismodegib (Figure 1; Kim et al., wood et al., 2015). This is an interesting 2013). Perhaps the structural models of result with obvious therapeutic implica- Taipale, J., Chen, J.K., Cooper, M.K., Wang, B., Mann, R.K., Milenkovic, L., Scott, M.P., and the mutant SMO proteins presented in tions and is consistent with their previous Beachy, P.A. (2000). Nature 406, 1005–1009. these papers will inform the rational work showing that the aPKC-i/l inhibitor design of a new generation of SMO inhib- is effective against cyclopamine-resistant Yauch, R.L., Dijkgraaf, G.J., Alicke, B., Januario, T., Ahn, C.P., Holcomb, T., Pujara, K., Stinson, J., itors with improved resistance profiles. BCC cell lines (Atwood et al., 2013). Gli Callahan, C.A., Tang, T., et al. (2009). Science However, activation of HH signaling protein can also be targeted with arsenic 326, 572–574.

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