Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma

Brinkhuizen, Tjinta; Reinders, Marie G H C; Geel, Michel van; Hendriksen, Annelot J L; Paulussen, Aimée D C; Winnepenninckx, Véronique; Keymeulen, Kristien; Soetekouw, Patricia M.M.B.; Steensel, M.A.M. van; Mosterd, Klara

doi:10.1016/j.jaad.2014.08.001

Cited by 62 publications

(38 citation statements)

References 3 publications

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“…However, some patients’ basal cell carcinomas have acquired resistance to vismodegib [33, 46, 47]. Therefore, therapeutic agents that target downstream molecules in the Hh signaling pathway, distal to SMO, are being developed [38].…”

Section: Discussionmentioning

confidence: 99%

Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

Cohen

Kurzrock

2015

Dermatol Ther (Heidelb)

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IntroductionMerkel cell carcinoma is a neuroendocrine malignancy. Suppressor of fused (SUFU) is a tumor suppressor oncogene that participates in the Hedgehog (Hh) signaling pathway. The aim of the study was to describe a patient whose Merkel cell carcinoma demonstrated a SUFU genomic alteration.Case StudyThe Hh signaling pathway is involved in the pathogenesis of several tumors, including nevoid basal cell carcinoma syndrome that is associated with an alteration of the patched-1 (PTCH1) gene. Targeted molecular therapy against smoothened (SMO) with vismodegib has been shown to be an effective therapeutic intervention for patients with PTCH-1 mutation. The reported patient was presented with metastatic Merkel cell carcinoma. Analysis of his tumor, using a next-generation sequencing-based assay, demonstrated a genomic aberration of SUFU protein, a component of the Hh signaling pathway that acts downstream to SMO and, therefore, is unlikely to be responsive to vismodegib. Of interest, arsenic trioxide or bromo and extra C-terminal inhibitors impact signals downstream to SUFU, making this aberration conceivably druggable. His tumor has initially been managed with chemotherapy (carboplatin and etoposide) and subsequent radiation therapy is planned.ConclusionThe pathogenesis of Merkel cell carcinoma is multifactorial, and related to ultraviolet radiation exposure, immunosuppression, and Merkel cell polyomavirus. We report a patient with a mutation in SUFU, a potentially actionable component of the Hh signaling pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s13555-015-0074-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

Cohen

Kurzrock

2015

Dermatol Ther (Heidelb)

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“…Both treatment arms successfully met the primary end point of ORR as assessed by central review at the time of primary analysis (cutoff of 28 June 2013). An objective response was achieved by 20 of 55 patients (36%; 95% CI: 24-50) in the 200 mg treatment group and 39 of 116 patients (34%; 95% CI: [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] in the 800 mg treatment group as assessed by central review. No substantial difference in ORR could be found in different subgroups stratified by geographic location or histologic subtype.…”

Section: Overview Of the Bolt Trialmentioning

confidence: 99%

“…This reactivation is mainly caused by SMO mutations and less so by a gain-of-function mutation in Gli2 as well as a loss-of-function mutation in suppressor of fused, which negatively regulates the hedgehog pathway. In a case report of a 68-year-old woman who had complete regression of her laBCC after 16 weeks of vismodegib 150 mg daily and subsequent development of recurrent tumors around the primary site after 20 weeks, different novel heterozygous missense SMO mutations were identified that were not found in pretreatment tumor tissue [33].…”

Section: Post-trial Concerns and Present Challengesmentioning

confidence: 99%

Treatment of Advanced Basal Cell Carcinoma with Sonidegib: Perspective from the 30-Month Update of the BOLT Trial

Chen¹,

Aria²,

Silapunt³

et al. 2017

Future Oncol.

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Sonidegib, a hedgehog pathway inhibitor, was approved by the US FDA for the treatment of locally advanced basal cell carcinoma which cannot be readily treated with surgery or radiotherapy. The pharmacology and pharmacokinetics of sonidegib will be discussed in this review. Additionally, an in-depth analysis of the BOLT trial and data from the 30-month update will be included. This will serve as an update to a previously published article which reported the 12-month update of the BOLT trial. BackgroundBasal cell carcinoma (BCC) is the most common skin cancer in humans. Annually, there are 2.8 million cases that result in approximately 3000 deaths [1]. The use of surgical excision for the treatment of BCC results in a 5-year cure rate close to 90% [2,3]. The 5-year recurrence rate decreases to 0.7-2.4% when Mohs micrographic surgery (MMS) is performed [4][5][6][7]. Alternative nonsurgical approaches include cryotherapy, electrodesiccation and curettage, photodynamic therapy, radiation, or topical agents such as imiquimod or 5-fluorouracil. These options usually confer a lower cure rate and lack confirmation of tumor clearance on histology. Although metastasis of BCC has a very low incidence of 0.0028-0.

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“…A biopsy from one of the metastatic lesions from the vismodegib-resistant metastatic medulloblastoma mentioned above revealed an acquired mutation in SMO that disrupted drug binding (69). To date, this is the only functionally characterized mechanism of resistance to a SMO inhibitor in the clinic; however, SMO mutations were recently observed in a vismodegib-resistant patient with BCC (72). Preclinical models of medulloblastoma have been used to investigate further potential mechanisms of resistance to the SMO inhibitors vismodegib and sonidegib, and have identified alternative genetic alterations including amplification of Gli2, an effector and downstream target of SMO, or activation of an alternative pathway such as the PI3K pathway (73), which was subsequently demonstrated to reduce, but not completely block, the response to vismodegib (74).…”

Section: Smo Inhibitor Resistance In Bccmentioning

confidence: 99%

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Basset-Séguin

Sharpe

Sauvage

2015

Molecular Cancer Therapeutics

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Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated antitumoral activity, but treatment may be limited in duration by a number of side effects, and it is not yet established whether these agents are truly curative or whether continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability, as well as neoadjuvant use of Hh pathway inhibitors, are currently under investigation. Here, we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC.

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Acquired resistance to the Hedgehog pathway inhibitor vismodegib due to smoothened mutations in treatment of locally advanced basal cell carcinoma

Cited by 62 publications

References 3 publications

Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

Merkel Cell Carcinoma with a Suppressor of Fused (SUFU) Mutation: Case Report and Potential Therapeutic Implications

Treatment of Advanced Basal Cell Carcinoma with Sonidegib: Perspective from the 30-Month Update of the BOLT Trial

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

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