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

Population Health Sciences

Research output: Contribution to journal › Article › peer-review

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 : an official journal of the American Association for Cancer Research
Volume	28
Issue number	7
DOIs	https://doi.org/10.1158/1078-0432.CCR-21-3764
Publication status	Published - 1 Apr 2022

Keywords

Anilides/therapeutic use
Antineoplastic Agents/pharmacology
Carcinoma, Basal Cell/drug therapy
Cerebellar Neoplasms/drug therapy
Hedgehog Proteins/genetics
Humans
Pyridines
Skin Neoplasms/drug therapy

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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 : an official journal of the American Association for Cancer Research, 28(7), 1422-1432. https://doi.org/10.1158/1078-0432.CCR-21-3764

@article{f0f8fad9ef0c4fb3b8a38f5fb1cf5ca3,

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.",

keywords = "Anilides/therapeutic use, Antineoplastic Agents/pharmacology, Carcinoma, Basal Cell/drug therapy, Cerebellar Neoplasms/drug therapy, Hedgehog Proteins/genetics, Humans, Pyridines, Skin Neoplasms/drug therapy",

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 = "Funding Information: outside the submitted work. S. Mourah reports personal fees from Roche, Pierre Fabre, Biocartis, and Novartis outside the submitted work. F. Bouquet reports other support from F. Hoffmann-La Roche during the conduct of the study, as well as other support from F. Hoffmann-La Roche outside the submitted work. A. Savina reports nonfinancial support from AstraZeneca during the conduct of the study, as well as personal fees from AstraZeneca outside the submitted work. S. Monestier reports personal fees from BMS, MSD, Sanofi, Pierre Fabre Oncologie, and Roche outside the submitted work. L. Mortier reports personal fees from Sun Pharma during the conduct of the study, as well as personal fees from MSD, Novartis, Pierre Fabre, and BMS outside the submitted work. N. Meyer reports grants and personal fees from MSD and BMS, as well as personal fees from Novartis, Sun Pharma, Pierre Fabre, Sanofi, and Merck outside the submitted work. C. Robert reports personal fees from Roche, Novartis, BMS, MSD, Pierre Fabre, and Sanofi outside the submitted work. F. Herms reports personal fees from Sun Pharma and Sanofi outside the submitted work. F.J. de Sauvage reports other support from Genentech and Roche during the conduct of the study. L. Flatz reports grants from Swiss National Science Foundation and Swiss Cancer League during the conduct of the study, as well as grants from Hookipa Pharma and personal fees from Novartis, Bristol Myers Squibb, and Sanofi outside the submitted work. N. Basset-Seguin reports grants from Genentech during the conduct of the study. No disclosures were reported by the other authors. Funding Information: S.I. Nikolaev was supported by grant Foundation ARC 2017, Foundation Gustave Roussy and Swiss Cancer Research Foundation KFC-3985-08-2016. N. Basset-Seguin was supported by a Roche Genentech Grant. L. Flatz was supported by the Swiss National Science Foundation grant PP00P3_157448 and Research Fund of the Kantonsspital St. Gallen (11/19). 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 : an official journal of the American Association for Cancer Research",

issn = "1078-0432",

publisher = "American Association for Cancer Research Inc.",

number = "7",

}

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 : an official journal of the American Association for Cancer Research, vol. 28, no. 7, pp. 1422-1432. https://doi.org/10.1158/1078-0432.CCR-21-3764

Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma. / Yurchenko, Andrey A; Pop, Oltin T; Ighilahriz, Meriem et al.
In: Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 28, No. 7, 01.04.2022, p. 1422-1432.

Research output: Contribution to journal › Article › peer-review

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 - Funding Information: outside the submitted work. S. Mourah reports personal fees from Roche, Pierre Fabre, Biocartis, and Novartis outside the submitted work. F. Bouquet reports other support from F. Hoffmann-La Roche during the conduct of the study, as well as other support from F. Hoffmann-La Roche outside the submitted work. A. Savina reports nonfinancial support from AstraZeneca during the conduct of the study, as well as personal fees from AstraZeneca outside the submitted work. S. Monestier reports personal fees from BMS, MSD, Sanofi, Pierre Fabre Oncologie, and Roche outside the submitted work. L. Mortier reports personal fees from Sun Pharma during the conduct of the study, as well as personal fees from MSD, Novartis, Pierre Fabre, and BMS outside the submitted work. N. Meyer reports grants and personal fees from MSD and BMS, as well as personal fees from Novartis, Sun Pharma, Pierre Fabre, Sanofi, and Merck outside the submitted work. C. Robert reports personal fees from Roche, Novartis, BMS, MSD, Pierre Fabre, and Sanofi outside the submitted work. F. Herms reports personal fees from Sun Pharma and Sanofi outside the submitted work. F.J. de Sauvage reports other support from Genentech and Roche during the conduct of the study. L. Flatz reports grants from Swiss National Science Foundation and Swiss Cancer League during the conduct of the study, as well as grants from Hookipa Pharma and personal fees from Novartis, Bristol Myers Squibb, and Sanofi outside the submitted work. N. Basset-Seguin reports grants from Genentech during the conduct of the study. No disclosures were reported by the other authors. Funding Information: S.I. Nikolaev was supported by grant Foundation ARC 2017, Foundation Gustave Roussy and Swiss Cancer Research Foundation KFC-3985-08-2016. N. Basset-Seguin was supported by a Roche Genentech Grant. L. Flatz was supported by the Swiss National Science Foundation grant PP00P3_157448 and Research Fund of the Kantonsspital St. Gallen (11/19). 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.

KW - Anilides/therapeutic use

KW - Antineoplastic Agents/pharmacology

KW - Carcinoma, Basal Cell/drug therapy

KW - Cerebellar Neoplasms/drug therapy

KW - Hedgehog Proteins/genetics

KW - Humans

KW - Pyridines

KW - Skin Neoplasms/drug therapy

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

SN - 1078-0432

VL - 28

SP - 1422

EP - 1432

JO - Clinical cancer research : an official journal of the American Association for Cancer Research

JF - Clinical cancer research : an official journal of the American Association for Cancer Research

IS - 7

ER -

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

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