Author of

• 31446

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  P1.14 - Targeted Therapy (ID 182)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall

  • 31514

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    P1.14-60 - Statins Overcome Resistance to Tyrosine Kinase Inhibitors in Patient-Derived, Oncogene-Driven NSCLC Models (ID 2969)

    09:45 - 18:00  |  Author(s): Chihong Zhou
    • Abstract

    Background
    

    Despite the improved efficacy of newer generation targeted TKIs, nearly all patients with EGFR- and ALK-driven NSCLC eventually acquire resistance and succumb to the refractory metastatic disease. Previous studies have shown that simvastatin has more potent antitumor effects compared to other statins. The objective of this study was to determine whether simvastatin could overcome TKI resistance using in vitro and in vivo NSCLC models.

    Method
    

    Human NSCLC cell lines A549 (KRAS G12S), H3255 (EGFR L858R), and H1975 (EGFR L858R and T790M) were treated with simvastatin either alone or in combination with an TKI. Antitumor effect was measured by growth inhibition by MTS assay and expression of molecular targets by immunoblots. Malignant pleural effusion and biopsied tumors were collected under an IRB-approved protocol and used for primary cell culture and generation of patient-derived xenograft models in NSG mice. Mice implanted with H1975 xenografts were treated with vehicle, simvastatin, osimertinib, or both. Mice engrafted with an ALK-TKI resistant PDX were treated with vehicle simvastatin, brigatinib, or both. Tumor growth was measured every other day for 28 days or the tumor volume reached ~2 cm³. Tumors were subjected to histomorphological assessment and immune blot analyses. All data are shown as mean ± standard deviation (SD). The two-sample t-test was used for continuous variables. All statistical tests were two-sided and a p-value less than 0.05 was considered statistically significant.

    Result
    

    We found that simvastatin alone had a strong antitumor effect in tested NSCLC cell lines, regardless of tumor genotypes. Simvastatin and osimertinib combination showed synergistic cytotoxic effect in these NSCLC cell lines and several primary culture of patient’s pleural effusion. Simvastatin alone reduced the tumor volume by 41% and 57% compared to controls in both the EGFR- and ALK-TKI resistant PDX models. In the H1975 xenograft model, simvastatin and osimertinib combination produced a greater reduction in tumor volume than osimertinib alone (P < 0.01). In an ALK TKI-resistant lung PDX model, simvastatin and brigatinib combination resulted in a greater reduction in tumor volume than brigatinib alone (P < 0.01) and showed a synergistic effect based on a simple multiplicative model of a fixed dose, two-drug combination.

    Conclusion
    

    Simvastatin displays anti-tumor activity in multiple EGFR and ALK TKI resistant models, and preliminary analysis suggests potential synergism with the two tested TKIs (osimertinib and brigatinib). Further study is needed to characterize the molecular mechanisms responsible for the statin-mediated anti-tumor effect and its interactions with TKIs.

• 30780

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  P2.03 - Biology (ID 162)

  • Event: WCLC 2019
  • Type: Poster Viewing in the Exhibit Hall
  • Track: Biology
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall

  • 30837

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    P2.03-55 - High Integrin α3 Expression Is Associated with Poor Prognosis in Patients with NSCLC (ID 2543)

    10:15 - 18:15  |  Author(s): Chihong Zhou
    • Abstract

    Background
    

    Integrin α3β1 belongs to a family of heterodimeric transmembrane glycoprotein receptors that mediates cell adhesion and cytoskeleton function. We recently showed that integrin α3β1 is a promising novel cancer biomarker and drug target in NSCLC. While the integrin α3 unit (INTA3) mediates the binding to various ligands and substrates, the integrin β1 unit (INTB1) mainly is primarily responsible for the complex biological functions. INTA3 only binds to INTB1 as the binding partner. This study was undertaken to evaluate if INTA3 expression was correlated with clinicopathological parameters and survival in patients with non-small cell lung cancer (NSCLC).

    Method
    

    Tissue microarrays (TMAs) were made from archival formalin-fixed and paraffin-embedded tissue blocks of 161 NSCLC patients, which included 91 adenocarcinoma (LUAD), 46 squamous carcinomas (LUSC), and 24 other histology types. TMA sections were stained for INTA3 expression using anti-integrin α3 antibody (ab131055, dilution 1:100; Abcam) by immunohistochemistry (IHC) stain. Staining intensity was graded as 0 (0-5%, negative), 1+ (6-20%, weak), 2+ (21-50%, moderate), and 3+ (51-100%, strong). Kaplan-Meier curves and log-rank test were used to compare overall survival of IHC score groups. To adjust for covariate imbalance between IHC score groups, propensity-score-weighted Kaplan-Meier curves and weighted Cox models were used. Logistic regression was used to study association between INTA3 expression and patient clinicopathological parameters.

    Result
    

    INTA3 IHC expression was detected in 107/161 (66.5%) of the NSCLC samples. Weak (1+), moderate (2+) and strong (3+) INTA3 expression was detected in 66 (41.0%), 33 (20.5%), and 8 (5.0%) cases, respectively. Kaplan-Meier curves indicated that weak (1+) and strong (3+) INTA3 expression was significantly associated with poor overall survival in NSCLC patients (p < 0.05 and p < 0.001, respectively). Propensity-score-weighted survival analysis demonstrated that INTA3 IHC expression (1+-3+) was associated with poor prognosis (HR = 1.39, 95% CI: 1.06-1.83, p =0.02) for all NSCLC patients, as well as in subgroups of female patients (HR =1.99, 95% CI: 1.32-3.01, p < 0.01), smokers (HR =2.46, 95% CI: 1.66-3.65 p < 0.01) and differentiation grade I&II (HR =3.0, 95% CI: 1.91-4.59 p < 0.01), but not in LUSC patients (p=0.11), LUAD patients (p=0.07), male patients (p=0.06), non-smokers (p=0.34), differentiation grade III (p=0.98). Logistic regression indicated that high INTA3 expression is associated with no smoke history (OR=2.7, 95% CI:1.3-5.7, p=0.01).

    Conclusion
    

    INTA3 was expressed in the majority of NSCLC by IHC and was associated with poor prognosis. Further study is warranted for targeting integrin α3(β1) in NSCLC.