Curis Inc (CRIS)

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Resistance in Medulloblastoma

The infamous 26YO

The authors found that a specific mutation in Smoothened (SMO) present in the tumor after relapse had no effect on Hedgehog signaling but did disrupt the ability of GDC-0449 to bind to SMO. Since SMO is the direct molecular target of GDC-0449, its inability to effectively bind to SMO in this patient likely led to the emergence of drug resistance. This work provides the first evidence that a family of receptors, of which SMO is included, may be subject to the development of drug resistance by mutation of a region of this receptor.

http://www.drugs.com/clinical_trials/curis-announces-gdc-0449-phase-clinical-data-published-new-england-journal-medicine-7989.html


" a family of receptors, of which SMO is included " "by mutation of a region of this receptor"

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Epub 2010 Dec 1
Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance.

* individual ultimately relapsed with a D473H resistance mutation in Smoothened (SMO)
* we substituted D473 with every amino acid and found that all functional mutants were resistant to GDC-0449
* resistance may also occur downstream of SMO

http://www.ncbi.nlm.nih.gov/pubmed/21123452