FREQUENCY AND GENOMIC ASPECTS OF INTRINSIC RESISTANCE TO VISMODEGIB IN LOCALLY ADVANCED BASAL CELL CARCINOMA
Andrey Yurchenko
(1, 2)
,
Oltin Pop
(3)
,
Meriem Ighilahriz
(4)
,
Ismael Padioleau
(2)
,
Fatemeh Rajabi
(2)
,
Hayley Sharpe
(5)
,
Nicolas Poulalhon
(6)
,
Brigitte Dreno
(7, 8)
,
Amir Khammari
(9, 10)
,
Marc Delord
(11)
,
Antonio Alberdi
(12)
,
Nadem Soufir
(13)
,
Maxime Battistella
(13)
,
Samia Mourah
(13)
,
Fanny Bouquet
(14)
,
Ariel Savina
(14)
,
Andrej Besse
(3)
,
Max Mendez-Lopez
(3)
,
Florent Grange
(15)
,
Sandrine Monestier
(16)
,
Laurent Mortier
(17)
,
Nicolas Meyer
(18)
,
Caroline Dutriaux
(19)
,
Caroline Robert
(20, 21)
,
Philippe Saïag
(22)
,
Florian Herms
(23)
,
Jerome Lambert
(13)
,
Fred de Sauvage
(24)
,
Nicolas Dumaz
(13)
,
Lukas Flatz
(3)
,
Nicole Basset-Seguin
(13)
,
Sergey Nikolaev
(20, 2)
1
U981 -
Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse
2 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie
3 Brustzentrum Kantonsspital St. Gallen
4 HIPI (UMR_S_976 / U976) - Immunologie humaine, physiopathologie & immunothérapie
5 The Babraham Institute [Cambridge, UK]
6 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
7 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
8 CIC Nantes - Centre d’Investigation Clinique de Nantes
9 INCIT - Immunology and New Concepts in ImmunoTherapy
10 CHU Nantes - Centre hospitalier universitaire de Nantes
11 Université Paris Diderot, Sorbonne Paris Cité, Paris, France
12 IRSL - Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH)
13 AP-HP - Hopital Saint-Louis [AP-HP]
14 Institut ROCHE [Boulogne-Billancourt]
15 CHU Reims - Centre Hospitalier Universitaire de Reims
16 TIMONE - Hôpital de la Timone [CHU - APHM]
17 INSERM U837 - Equipe 3 - Facteurs de persistance des cellules leucémique -
18 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
19 CHU Bordeaux [Bordeaux]
20 IGR - Institut Gustave Roussy
21 Oncologie dermatologique
22 Hôpital Ambroise Paré [AP-HP]
23 Service de Dermatologie [AP-HP Hôpital Saint-Louis]
24 Genentech, Inc.
2 PMNCO - Prédicteurs moléculaires et nouvelles cibles en oncologie
3 Brustzentrum Kantonsspital St. Gallen
4 HIPI (UMR_S_976 / U976) - Immunologie humaine, physiopathologie & immunothérapie
5 The Babraham Institute [Cambridge, UK]
6 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
7 CRCI2NA - Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers
8 CIC Nantes - Centre d’Investigation Clinique de Nantes
9 INCIT - Immunology and New Concepts in ImmunoTherapy
10 CHU Nantes - Centre hospitalier universitaire de Nantes
11 Université Paris Diderot, Sorbonne Paris Cité, Paris, France
12 IRSL - Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine ; ex- Institut Universitaire Hématologie-IUH)
13 AP-HP - Hopital Saint-Louis [AP-HP]
14 Institut ROCHE [Boulogne-Billancourt]
15 CHU Reims - Centre Hospitalier Universitaire de Reims
16 TIMONE - Hôpital de la Timone [CHU - APHM]
17 INSERM U837 - Equipe 3 - Facteurs de persistance des cellules leucémique -
18 CHU Toulouse - Centre Hospitalier Universitaire de Toulouse
19 CHU Bordeaux [Bordeaux]
20 IGR - Institut Gustave Roussy
21 Oncologie dermatologique
22 Hôpital Ambroise Paré [AP-HP]
23 Service de Dermatologie [AP-HP Hôpital Saint-Louis]
24 Genentech, Inc.
Andrey Yurchenko
- Function : Author
- PersonId : 805346
- ORCID : 0000-0002-2239-6902
Oltin Pop
- Function : Author
- PersonId : 821361
- ORCID : 0000-0001-8000-2310
Maxime Battistella
- Function : Author
- PersonId : 770105
- ORCID : 0000-0002-7053-7431
Samia Mourah
- Function : Author
- PersonId : 758625
- ORCID : 0000-0002-9283-1068
- IdRef : 139191690
Max Mendez-Lopez
- Function : Author
- PersonId : 821363
- ORCID : 0000-0002-4997-5621
Sandrine Monestier
- Function : Author
- PersonId : 786428
- ORCID : 0000-0003-4189-3127
Laurent Mortier
- Function : Author
- PersonId : 793850
- ORCID : 0000-0002-2644-1790
Nicolas Meyer
- Function : Author
- PersonId : 800819
- ORCID : 0000-0003-4519-8666
- IdRef : 16890084X
Caroline Robert
- Function : Author
- PersonId : 756200
- ORCID : 0000-0002-9493-0238
- IdRef : 077646215
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 5 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 which were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in 3 out of 5 IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyper-activation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on BCC cell line further confirmed that YAP1 overexpression increases 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 hyper-activation of HIPPO-YAP and WNT pathways.
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