Reference Detail

Ref Type

Journal Article

PMID

(25759019)

Authors

Sharpe HJ, Pau G, Dijkgraaf GJ, Basset-Seguin N, Modrusan Z, Januario T, Tsui V, Durham AB, Dlugosz AA, Haverty PM, Bourgon R, Tang JY, Sarin KY, Dirix L, Fisher DC, Rudin CM, Sofen H, Migden MR, Yauch RL, de Sauvage FJ

Title

Genomic analysis of smoothened inhibitor resistance in basal cell carcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer cell	27	3	2015 Mar 9	327-41	Cancer Cell

URL

Abstract Text

Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
ATR	M211T	missense	unknown	ATR M211T does not lie within any known functional domains of the Atr protein (UniProt.org). M211T has been identified in sequencing studies (PMID: 25528188, PMID: 25759019, PMID: 31748433), but has not been biochemically characterized and therefore, its effect on Atr protein function is unknown (PubMed, Mar 2024).
ATR	T2516I	missense	unknown	ATR T2516I lies within the PI3K/PI4K domain of the Atr protein (UniProt.org). T2516I has been identified in sequencing studies (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Atr protein function is unknown (PubMed, Feb 2024).
PIK3CA	P449L	missense	unknown	PIK3CA P449L lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). P449L has been identified in sequencing studies (PMID: 29032825, PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2024).
PIK3CA	P466S	missense	unknown	PIK3CA P466S lies within the C2 PI3K-type domain of the Pik3ca protein (UniProt.org). P466S has been identified in sequencing studies (PMID: 25759019, PMID: 22622578), but has not been biochemically characterized and therefore, its effect on Pik3ca protein function is unknown (PubMed, Mar 2024).
ROS1	E2308K	missense	unknown	ROS1 E2308K lies within the cytoplasmic domain of the Ros1 protein (UniProt.org). E2308K has been identified in sequencing studies (PMID: 25759019, PMID: 26950094, PMID: 35130390), but has not been biochemically characterized and therefore, its effect on Ros1 protein function is unknown (PubMed, Mar 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References