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F. Meric-Bernstam

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    Best of Posters - IASLC Selection - Part 2 (ID 263)

    • Event: WCLC 2013
    • Type: Exhibit Showcase Session
    • Track:
    • Presentations: 1
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      P2.06-032 - SMO mutations occur in non-small cell lung cancer (NSCLC) and may respond to hedgehog inhibitors (ID 2483)

      09:55 - 10:25  |  Author(s): F. Meric-Bernstam

      • Abstract
      • Slides

      Smoothened (SMO) is a 7-membrane spanning receptor involved in the hedgehog signaling pathway. In the absence of Patched inhibition, SMO accumulates and inhibits proteolytic cleavage of transcription factors. We previously identified a lung cancer patient with SMO mutation (Patient A, Table 1) and successfully treated him with erivedge, a hedgehog inhibitor. We therefore sought to determine the incidence of SMO mutations in The Cancer Genome Atlas (TCGA) lung cohorts, identify additional NSCLC patients with SMO mutations, and initiate therapy with hedgehog inhibition as proof-of-concept.

      TCGA databases for lung adenocarcinoma (n=230) and squamous cell carcinoma (n=178) were interrogated for SMO mutations and hedgehog pathway dyregulation. Mutations were determined by whole exome sequencing. Copy number was assessed by GISTIC 2.0 (scores of 2 considered high level amplification). The lung SMO mutation patients were undergoing treatment at M.D. Anderson Cancer Center Thoracic Clinic for metastatic/refractory disease. Mutations in hotspot regions of 46 cancer-related genes including SMO was performed as part of their clinical diagnostic evaluation (Ion AmpliSeq Cancer Panel; Life Technologies, CA).

      In TCGA lung adenocarcinomas, alterations in SMO (mutation, amplification, mRNA overexpression) were observed in 12.2% of tumors. The incidence of SMO mutations was 2.6% and SMO gene amplifications 5%. SMO mutations and amplifications strongly correlated with sonic hedgehog gene dysregulation (p<0.0001). In TCGA squamous cell, SMO was altered in 10.1% of tumors, primarily via mRNA upregulation. Only 1 SMO missense mutation was identified in the Lung SCC cohort (D209Y). We identified 3 NSCLC patients with SMO mutations (Table 1) by the 46-gene panel. Patient A was treated with erivedge as he had a concomitant localized basal cell carcinoma (BCC) with a significant reduction in tumor burden. He continues to respond to therapy after 14 weeks. It is possible that Patient A’s NSCLC-SCC was misidentified and that this was metastatic BCC or that this is a germline variant. Germ-line mutation analysis is underway. However, the precise SMO mutation in Patient A was also identified in a lung adenocarcinoma Patient C (Table 1). Two additional SMO-mutated patients have just initiated erivedge and updates on their status will be provided at WLCC.

      Table 1
      Patient Biopsy site SMO mutation Reported Histology Duration of Erivedge Therapy Response to Erivedge
      A Lung Codon 641, exon 11 (CCT to GCT) p. Pro641Ala NSCLC SCC 14 weeks PR
      A Skin lesion Codon 641, exon 11 (CCT to GCT) p. Pro641Ala BCC 14 weeks CR
      B AP window lymph node Codon 525, exon 9 (ATG to TTG) p.Met525Leu NSCLC Adenoca pending pending
      C Axillary lymph node Codon 641, exon 11 (CCT to GCT) p.Pro241Ala NSCLC Adenoca pending pending

      SMO mutations and pathway alterations occur in NSCLC and may be an actionable target with hedgehog inhibitors; a clinical trial is under development. Screening lung SCC tumors for SMO mutations is recommended to prevent misdiagnosis of metastatic BCC. Additional analysis of hedgehog signaling pathway alterations is underway and will subsequently be reported.

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