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 Cancer cell
Vol 27
Issue 3
Date 2015 Mar 9
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 Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
P875S missense unknown BRCA1 P875S lies within the Rad51-binding region of the Brca1 protein (PMID: 22737296). P875S has been identified in sequencing studies (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Brca1 protein function is unknown (PubMed, Nov 2018).
L155F missense unknown ERBB4 L155F lies within the extracellular domain of the Erbb4 protein (UniProt.org). L155F has been identified in sequencing studies (PMID: 25759019), but has not been biochemically charcterized and therefore, its effect on Erbb4 protein function is unknown (PubMed, Dec 2018).
P563S missense unknown SETBP1 P563S does not lie within any known functional domains of the Setbp1 protein (PMID: 23222956). P563S has been identified in sequencing studies (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Setbp1 protein function is unknown (PubMed, Sep 2018).
Y47S missense unknown SMARCB1 Y47S lies within the DNA-binding region of the Smarcb1 protein (UniProt.org). Y47S has been identified in sequencing studies (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smarcb1 protein function is unknown (PubMed, Feb 2019).
A459V missense gain of function - predicted SMO A459V does not lie within any known functional domains of the Smo protein (UniProt.org). A459V is predicted to confer a gain of function to the Smo protein as demonstrated by increased Smo activity and also confers resistance to Hedgehog inhibitors in cell culture (PMID: 25759019). Y
C469Y missense unknown SMO C469Y lies within the drug-binding pocket of the Smo protein (PMID: 25759019). C469Y has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Jul 2018). Y
D384N missense unknown SMO D384N lies within the drug-binding pocket of the Smo protein (PMID: 25759019). D384N has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Jul 2018). Y
I408V missense unknown SMO I408V lies within the drug-binding pocket of the Smo protein (PMID: 25759019). I408V has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized, and therefore, its effect on Smo protein function is unknown (PubMed, Sep 2018). Y
N219D missense unknown SMO N219D lies within the drug-binding pocket of the Smo protein (PMID: 25759019). N219D has been demonstrated to confer resistance to Hedgehog pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Jul 2018). Y
S387N missense unknown SMO S387N lies within the drug-binding pocket of the Smo protein (PMID: 25759019). S387N has been demonstrated to confer resistance to Hh pathway inhibitors (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Smo protein function is unknown (PubMed, Feb 2019). Y
T241M missense gain of function - predicted SMO T241M does not lie within any known functional domains of the Smo protein (UniProt.org). T241M is predicted to confer a gain of function to the Smo protein, as demonstrated by increased Smo activity and also confers resistance to Hedgehog inhibitors in cell culture (PMID: 25759019). Y
P572S missense unknown STAG2 P572S does not lie within any known functional domains of the Stag2 protein (UniProt.org). P572S has been identified in sequencing studies (PMID: 25759019), but has not been biochemically characterized and therefore, its effect on Stag2 protein function is unknown (PubMed, Mar 2019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMO A459V Advanced Solid Tumor decreased response Vismodegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO A459V on the background of PTCH1 and TP53 deletion demonstrated reduced response to Erivedge (vismodegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO I408V Advanced Solid Tumor decreased response Vismodegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO I408V on the background of PTCH1 and TP53 deletion demonstrated reduced response to Erivedge (vismodegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO C469Y Advanced Solid Tumor decreased response Vismodegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO C469Y on the background of PTCH1 and TP53 deletion demonstrated reduced response to Erivedge (vismodegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO S387N sarcoma decreased response Vismodegib Preclinical Actionable In a preclinical study, mouse sarcoma cell lines over expressing SMO S387N demonstrated reduced response to Erivedge (vismodegib) induced Hedgehog pathway inhibition in cell culture (PMID: 25759019). 25759019
SMO T241M Advanced Solid Tumor sensitive JQ1 Preclinical Actionable In a preclinical study, JQ1 inhibited proliferation of primary cerebellar granule neuron precursor cells over expressing SMO T241M on the background of PTCH1 and TP53 deletion in cell culture (PMID: 25759019). 25759019
SMO N219D sarcoma decreased response Vismodegib Preclinical Actionable In a preclinical study, mouse sarcoma cell lines over expressing SMO N219D demonstrated reduced response to Erivedge (vismodegib) induced Hedgehog pathway inhibition in cell culture (PMID: 25759019). 25759019
SMO A459V Advanced Solid Tumor sensitive JQ1 Preclinical Actionable In a preclinical study, JQ1 inhibited proliferation of primary cerebellar granule neuron precursor cells over expressing SMO A459V on the background of PTCH1 and TP53 deletion in cell culture (PMID: 25759019). 25759019
SMO T241M Advanced Solid Tumor decreased response Vismodegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO T241M on the background of PTCH1 and TP53 deletion demonstrated reduced response to Erivedge (vismodegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO T241M Advanced Solid Tumor decreased response Taladegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO T241M on the background of PTCH1 and TP53 deletion demonstrated reduced response to LY2940680 induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO C469Y Advanced Solid Tumor decreased response Sonidegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO C469Y on the background of PTCH1 and TP53 deletion demonstrated reduced response to Odomzo (sonidegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO I408V Advanced Solid Tumor decreased response Sonidegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO I408V on the background of PTCH1 and TP53 deletion demonstrated reduced response to Odomzo (sonidegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO W281C Advanced Solid Tumor decreased response Taladegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO W281C on the background of PTCH1 and TP53 deletion demonstrated reduced response to LY2940680 induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO C469Y Advanced Solid Tumor sensitive JQ1 Preclinical Actionable In a preclinical study, JQ1 inhibited proliferation of primary cerebellar granule neuron precursor cells over expressing SMO C469Y on the background of PTCH1 and TP53 deletion in cell culture (PMID: 25759019). 25759019
SMO T241M Advanced Solid Tumor decreased response Sonidegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO T241M on the background of PTCH1 and TP53 deletion demonstrated reduced response to Odomzo (sonidegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO A459V Advanced Solid Tumor decreased response Taladegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO A459V on the background of PTCH1 and TP53 deletion demonstrated reduced response to LY2940680 induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO I408V Advanced Solid Tumor decreased response Taladegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO I408V on the background of PTCH1 and TP53 deletion demonstrated reduced response to LY2940680 induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO V321M Advanced Solid Tumor decreased response Taladegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO T241M on the background of PTCH1 and TP53 deletion demonstrated reduced response to LY2940680 induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO W281C Advanced Solid Tumor decreased response Sonidegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO W281C on the background of PTCH1 and TP53 deletion demonstrated reduced response to Odomzo (sonidegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO A459V Advanced Solid Tumor decreased response Sonidegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO A459V on the background of PTCH1 and TP53 deletion demonstrated reduced response to Odomzo (sonidegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO W281C Advanced Solid Tumor sensitive JQ1 Preclinical Actionable In a preclinical study, JQ1 inhibited proliferation of primary cerebellar granule neuron precursor cells over expressing SMO W281C on the background of PTCH1 and TP53 deletion in cell culture (PMID: 25759019). 25759019
SMO D384N sarcoma decreased response Vismodegib Preclinical Actionable In a preclinical study, mouse sarcoma cell lines over expressing SMO D384N demonstrated reduced response to Erivedge (vismodegib) induced Hedgehog pathway inhibition in cell culture (PMID: 25759019). 25759019
SMO C469Y Advanced Solid Tumor decreased response Taladegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO C469Y on the background of PTCH1 and TP53 deletion demonstrated reduced response to LY2940680 induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO V321M Advanced Solid Tumor decreased response Sonidegib Preclinical Actionable In a preclinical study, primary cerebellar granule neuron precursor cells over expressing SMO C469Y on the background of PTCH1 and TP53 deletion demonstrated reduced response to Odomzo (sonidegib) induced growth inhibition in cell culture (PMID: 25759019). 25759019
SMO I408V Advanced Solid Tumor sensitive JQ1 Preclinical Actionable In a preclinical study, JQ1 inhibited proliferation of primary cerebellar granule neuron precursor cells over expressing SMO I408V on the background of PTCH1 and TP53 deletion in cell culture (PMID: 25759019). 25759019
SMO V321M Advanced Solid Tumor sensitive JQ1 Preclinical Actionable In a preclinical study, JQ1 inhibited proliferation of primary cerebellar granule neuron precursor cells over expressing SMO V321M on the background of PTCH1 and TP53 deletion in cell culture (PMID: 25759019). 25759019