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M.J. Seckl



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    O21 - SCLC II (ID 119)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O21.01 - A multicenter phase III randomized double-blind placebo controlled trial of pravastatin added to first-line standard chemotherapy in patients with small cell lung cancer (SCLC) (ID 1568)

      16:15 - 16:25  |  Author(s): M.J. Seckl

      • Abstract
      • Presentation
      • Slides

      Background

      Most SCLC patients initially respond to chemotherapy but then relapse and die so new therapies are urgently required. Pre-clinical data shows statins induce growth arrest and apoptosis in SCLC and several other tumour cell types and are additive with chemotherapy. This may in part be due to impaired Ras superfamily function as statins deplete mevalonate, reducing geranylgeranylation and farnesylation of these proteins. We therefore undertook this large pragmatic phase III trial in SCLC patients to determine if overall survival (OS) was affected by the addition of pravastatin to standard treatment.

      Methods
      Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice but recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity.

      Results
      Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed >4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Unblinded results showing the effect of pravastatin on OS, PFS, local PFS and toxicity will be presented.

      Conclusion
      This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients.

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    P3.01 - Poster Session 3 - Cancer Biology (ID 147)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.01-009 - FGF-2 induces chemoresistance in model and lung cancer cells through S6K2/hnRNPA1-mediated enhanced translation of anti-apoptotic proteins (ID 2252)

      09:30 - 09:30  |  Author(s): M.J. Seckl

      • Abstract

      Background
      Most patients die from lung cancer because of chemoresistant metastatic disease. We have previously identified the importance of fibroblast growth factor 2 (FGF2) /S6 kinase 2 (S6K2) signalling in mediating multidrug resistance in lung cancer through enhanced translation of antiapoptotic proteins, such as BCL-XL and XIAP. Here we investigate the downstream mediator(s) of this translational response and demonstrate its relevance in a lung cancer tissue array.

      Methods
      We used tandem affinity purification using S6K2 as bait as well as quantitative phospho-proteomics in the presence and absence of FGF2 stimulation in small cell lung cancer and HEK 293 cells to identify new S6K2 interactors and downstream mediators of the FGF2 pathway. Interactors were validated by co-immunopreciptation experiments and their functional significance examined by siRNA and expression of wild-type or phosphomutant forms. The clinical significance of our in vitro findings were examined in lung cancer tissue arrays.

      Results
      Here, we show that S6K2 interacts with and phosphorylates the heteronuclear ribonuclear protein hnRNPA1 on Ser 4 and 6. This increases the association of this protein with BCL-XL and XIAP mRNAs to promote their nuclear export while de-repressing their translation. A non-phosphorylatible S4/6A hnRNPA1 mutant prevented this process from occurring and impaired the pro-survival activity of FGF2/S6K2 signalling. Following phosphorylation and transfer to the cytoplasm in complex with mRNAs, phospho-hnRNPA1 associates with 14-3-3 to be sumoylated on K189 within a multi-protein complex involving UBC9. This targets hnRNPA1 for re-import into the nucleus in a caryopherin-dependent manner, a step that is essential for translational derepression of target mRNAs. Our in vitro findings predicted that in cancer cells where FGF2/S6K2 signalling is switched on, hnRNPA1 would be predominantly localised to the nucleus and cytoplasmic expression of anti-apoptotic proteins such as BCL-XL would be increased. To test this hypothesis, we stained a NSCLC tissue array for S6K2, hnRNPA1 and BCL-XL expression. Strikingly, this revealed that increased S6K2 expression tightly correlated with decreased cytoplasmic hnRNPA1 and increased BCL-XL levels.

      Conclusion
      FGF-2/S6K2 signalling promotes the nucleo-cytoplasmic cycling of hnRNPA1 to promote tumour cell survival through increased translation of the anti-apoptotic proteins BCL-XL and XIAP. Our immunohistochemical findings in NSCLC suggests that tumours which show absence of cytoplasmic hnRNPA1 in the presence of increased S6K2 and Bcl-XL expression might respond better to FGF receptor inhibitors.