Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

Andrey A. Yurchenko; Oltin T. Pop; Meriem Ighilahriz; Ismael Padioleau; Fatemeh Rajabi; Hayley J. Sharpe; Nicolas Poulalhon; Brigitte Dreno; Amir Khammari; Marc Delord; Antonio Alberti; Nadem Soufir; Maxime Battistella; Samia Mourah; Fanny Bouquet; Ariel Savina; Andrej Besse; Max Mendez-Lopez; Florent Grange; Sandrine Monestier; Laurent Mortier; Nicolas Meyer; Caroline Dutriaux; Caroline Robert; Philippe Saiag; Florian Herms; Jerome Lambert; Frederic J. de Sauvage; Nicolas Dumaz; Lukas Flatz; Nicole Basset-Seguin; Sergey I. Nikolaev

doi:10.1158/1078-0432.CCR-21-3764

Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

Andrey A. Yurchenko, Oltin T. Pop, Meriem Ighilahriz, Ismael Padioleau, Fatemeh Rajabi, Hayley J. Sharpe, Nicolas Poulalhon, Brigitte Dreno, Amir Khammari, Marc Delord, Antonio Alberti, Nadem Soufir, Maxime Battistella, Samia Mourah, Fanny Bouquet, Ariel Savina, Andrej Besse, Max Mendez-Lopez, Florent Grange, Sandrine MonestierLaurent Mortier, Nicolas Meyer, Caroline Dutriaux, Caroline Robert, Philippe Saiag, Florian Herms, Jerome Lambert, Frederic J. de Sauvage, Nicolas Dumaz, Lukas Flatz, Nicole Basset-Seguin, Sergey I. Nikolaev

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5 Citations (Scopus)

Abstract

Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

Original language	English
Pages (from-to)	1422-1432
Number of pages	11
Journal	Clinical Cancer Research
Volume	28
Issue number	7
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-3764
Publication status	Published - 1 Apr 2022

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10.1158/1078-0432.CCR-21-3764

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Yurchenko, A. A., Pop, O. T., Ighilahriz, M., Padioleau, I., Rajabi, F., Sharpe, H. J., Poulalhon, N., Dreno, B., Khammari, A., Delord, M., Alberti, A., Soufir, N., Battistella, M., Mourah, S., Bouquet, F., Savina, A., Besse, A., Mendez-Lopez, M., Grange, F., ... Nikolaev, S. I. (2022). Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma. Clinical Cancer Research, 28(7), 1422-1432. https://doi.org/10.1158/1078-0432.CCR-21-3764

@article{49cabb68b2b74a25b8109d292f91bd94,

title = "Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma",

abstract = "Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.",

author = "Yurchenko, {Andrey A.} and Pop, {Oltin T.} and Meriem Ighilahriz and Ismael Padioleau and Fatemeh Rajabi and Sharpe, {Hayley J.} and Nicolas Poulalhon and Brigitte Dreno and Amir Khammari and Marc Delord and Antonio Alberti and Nadem Soufir and Maxime Battistella and Samia Mourah and Fanny Bouquet and Ariel Savina and Andrej Besse and Max Mendez-Lopez and Florent Grange and Sandrine Monestier and Laurent Mortier and Nicolas Meyer and Caroline Dutriaux and Caroline Robert and Philippe Saiag and Florian Herms and Jerome Lambert and {de Sauvage}, {Frederic J.} and Nicolas Dumaz and Lukas Flatz and Nicole Basset-Seguin and Nikolaev, {Sergey I.}",

note = "Publisher Copyright: 2022 The Authors; Published by the American Association for Cancer Research",

year = "2022",

month = apr,

day = "1",

doi = "10.1158/1078-0432.CCR-21-3764",

language = "English",

volume = "28",

pages = "1422--1432",

journal = "Clinical Cancer Research",

issn = "1078-0432",

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Yurchenko, AA, Pop, OT, Ighilahriz, M, Padioleau, I, Rajabi, F, Sharpe, HJ, Poulalhon, N, Dreno, B, Khammari, A, Delord, M, Alberti, A, Soufir, N, Battistella, M, Mourah, S, Bouquet, F, Savina, A, Besse, A, Mendez-Lopez, M, Grange, F, Monestier, S, Mortier, L, Meyer, N, Dutriaux, C, Robert, C, Saiag, P, Herms, F, Lambert, J, de Sauvage, FJ, Dumaz, N, Flatz, L, Basset-Seguin, N & Nikolaev, SI 2022, 'Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma', Clinical Cancer Research, vol. 28, no. 7, pp. 1422-1432. https://doi.org/10.1158/1078-0432.CCR-21-3764

TY - JOUR

T1 - Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

AU - Yurchenko, Andrey A.

AU - Pop, Oltin T.

AU - Ighilahriz, Meriem

AU - Padioleau, Ismael

AU - Rajabi, Fatemeh

AU - Sharpe, Hayley J.

AU - Poulalhon, Nicolas

AU - Dreno, Brigitte

AU - Khammari, Amir

AU - Delord, Marc

AU - Alberti, Antonio

AU - Soufir, Nadem

AU - Battistella, Maxime

AU - Mourah, Samia

AU - Bouquet, Fanny

AU - Savina, Ariel

AU - Besse, Andrej

AU - Mendez-Lopez, Max

AU - Grange, Florent

AU - Monestier, Sandrine

AU - Mortier, Laurent

AU - Meyer, Nicolas

AU - Dutriaux, Caroline

AU - Robert, Caroline

AU - Saiag, Philippe

AU - Herms, Florian

AU - Lambert, Jerome

AU - de Sauvage, Frederic J.

AU - Dumaz, Nicolas

AU - Flatz, Lukas

AU - Basset-Seguin, Nicole

AU - Nikolaev, Sergey I.

N1 - Publisher Copyright: 2022 The Authors; Published by the American Association for Cancer Research

PY - 2022/4/1

Y1 - 2022/4/1

N2 - Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

AB - Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

UR - http://www.scopus.com/inward/record.url?scp=85128001023&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-21-3764

DO - 10.1158/1078-0432.CCR-21-3764

M3 - Article

C2 - 35078858

AN - SCOPUS:85128001023

SN - 1078-0432

VL - 28

SP - 1422

EP - 1432

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 7

ER -

Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

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