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Derek Richard
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-01 - Clinical Relevance of Targeting Proteins Required for Mitotic Progression to Improve Chemotherapy Response in Non-Small Cell Lung Cancer (ID 1565)
09:45 - 18:00 | Author(s): Derek Richard
- Abstract
Background
Lung cancer is the leading cause of cancer-related mortality worldwide with a ~14% 5-year survival rate. Patients with non-small cell lung cancer (NSCLC), may undergo surgery followed by platinum-based chemotherapy for resectable disease, chemoradiotherapy for locally advanced disease, systemic treatment for advanced disease and palliative care. The primary issue with chemotherapy is that only 20-40% of patients have responsive disease. Although combinations with immunotherapy can enhance drug response in advanced disease, new strategies are needed to (1) identify which patients are most likely to benefit from platinum based therapy and (2) enhance the effectiveness of the current drug strategies.
Herein we describe cell division cycle associated protein-3 (CDCA3) and CDCA8 as a novel prognostic factors and therapeutic targets to delay or prevent platinum resistance in NSCLC. Both CDCA3 and CDCA8 are key regulators of the cell cycle mediating mitotic entry and progression. CDCA3 functions to enable cell entry into mitosis through degradation of the mitosis inhibitory factor WEE1. Whereas, CDCA8 promotes mitotic progression functioning in concert with the chromosomal passenger complex to ensure accurate chromosomal segregation.
Method
Tissue microarray (TMA), immunohistochemistry, Bioinformatics, Western blot, siRNA library, CRISPR-Cas9 knockout, cell viability, mass spectrometry.
Result
Our preliminary data point to CDCA3 and CDCA8 as novel therapeutic options in NSCLC. CDCA3 and CDCA8 protein are markedly elevated in NSCLC cases with heterogeneous staining associated with Ki67+ cases and strongly prognostic in adenocarcinoma cases. Bioinformatics analysis of clinical trial data (UT Lung SPORE cohort; observation arm vs adjunct chemotherapy arm) indicated that NSCLC patients with elevated CDCA3 and CDCA8 and treated with adjuvant chemotherapy had a poorer outcome than CDCA3low/CDCA8low patients. Accordingly, in vitro analysis of CDCA3 and CDCA8 expression in NSCLC cell lines identified a strong correlation with cisplatin sensitivity whereby CDCA3/CDCA8high cell lines have greater cisplatin IC50 values. Consistently, silencing of either CDCA3 or CDCA8 significantly enhanced cisplatin sensitivity. As a means to reduce either CDCA3 or CDCA8 levels in tumours, we identified that, for CDCA3 in particular, cisplatin induces phosphorylation of CDCA3 (Ser222) which is dependent upon casein kinase 2 (CK2). Inhibition of CK2 with the small molecule CX-4945 (Senhwa Biosciences) abrogated CDCA3 phosphorylation and consequently suppressed CDCA3 levels. CK2 inhibition also suppressed CDCA8 levels whereby CDCA8 protein stability is dependent upon CDCA3. The sensitivity of cisplatin was enhanced by CX-4945 across a panel of 11 NSCLC cell lines, particularly in CDCA3/CDCA8low cell lines. Cisplatin efficacy was further enhanced in CDCA3 or CDCA8 depleted NSCLC cells.
Conclusion
Our data highlight CDCA3 and CDCA8 as novel factors mediating NSCLC cell proliferation and sensitivity to cisplatin. Our data also suggest that novel strategies to suppress CDCA3/CDCA8 protein levels, using agents such as CX-4945, might ultimately benefit NSCLC patient outcome by delaying or preventing cisplatin resistance.
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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
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P1.14-22 - SASH1, a Novel Prognostic and Predictive Factor for PARP Inhibitors in Lung Cancer (ID 744)
09:45 - 18:00 | Author(s): Derek Richard
- Abstract
Background
Genomic instability is a universal hallmark of all cancers. Many of the most commonly used chemotherapeutic agents target this genomic instability by directly damaging the DNA, which results in tumour cell death. Our previous work has revealed that loss of SASH1 is associated with impaired apoptosis and increased cellular proliferation. A new generation of drugs have been developed that target the DNA repair enzyme PARP to induce DNA damage and cell death. SASH1 (SAM and SH3 domain containing protein 1) has been described as a tumour suppressor and in support of this SASH1 mRNA levels are decreased in lung, breast, thyroid and colorectal cancers. Our data demonstrates that SASH1 functions in the repair of DNA damage and loss of SASH1 protein expression could be used as a companion diagnostic for PARP inhibitors.
Method
SASH1 IHC staining of lung cancer was correlated with patient survival. DNA damage repair was assessed following the depleted of SASH1 (siRNA). SASH1 protein levels in cell lines were correlated to PARP inhibitor sensitivity.
Result
A lung cancer tissue microarray (TMA) of 225 patients was assessed for SASH1 protein level. Low SASH1 levels were associated with an improved patient prognosis in adenocarcinoma on univariate analysis (p = 0.03). Analysis of DNA repair pathways demonstrated that SASH1 plays a role in homologous recombination (HR). Based on this observation, the impact of SASH1 expression on sensitivity to PARP inhibitors was explored. An inverse correlation between SASH1 levels and sensitivity to Olaparib was identified in lung cancer cell lines Figure 1 (R2 = 0.882). We subsequently analysed Olaparib sensitivity in a panel of SASH1 depleted lung cancer cells that demonstrated increased Olaparib sensitivity.
Conclusion
Our results indicate that SASH1 protein expression is a prognostic factor in lung cancer, high levels being associated with a worse prognosis in adenocarcinoma. Low SASH1 expression is associated with loss of HR and has the potential to be a predictive biomarker for sensitivity to PARP inhibitors in this disease.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-08 - Banf1 Predicts Lung Cancer Survival and Sensitivity to Platinum-Based Chemotherapy (ID 2146)
10:15 - 18:15 | Author(s): Derek Richard
- Abstract
Background
Barrier to autointegration factor 1 (BAF/Banf1) is a small, 10 kDa protein that functions as a non-specific DNA-binding homodimer and localises to the nuclear envelope during mitosis where it tethers DNA loops to the nuclear envelope.
Mutations in Banf1 are associated with the severe premature ageing syndrome, Néstor–Guillermo Progeria Syndrome. Previously, key proteins associated with other progeria syndromes have been shown to play a role in both tumourigenesis and ageing, and now more recently, Banf1 expression has been associated with poor gastric cancer survival. With lung cancers being the leading cause of cancer-related deaths worldwide, identifying markers of improved prognosis, particularly in association with specific chemotherapy treatments, is essential to maximising drug effectiveness and promoting patient survival.
Method
A variety of cell and tissue biology techniques including cellular Banf1 protein depletion and overexpression in a panel of lung cancer cell lines, drug treatments, immunofluorescence, immunoblotting and tissue microarray analysis, have been utilised in this study.
Result
Kaplan-Meier analysis of mRNA datasets from 1926 patients diagnosed with lung cancer show a statistically significant association (p=7.8e-12) between “low” Banf1 mRNA and increased median overall survival of patients at 88.7 months, compared with the 52-month median survival of the “high” Banf1 mRNA cohort.
Depletion of Banf1 in a panel of Non-Small Cell Lung Cancer (NSCLC) lines followed by cisplatin drug treatment demonstrated a heterogeneity of response, with a subset of cell lines experiencing improved survival while others displayed increased sensitivity to the drug compared with control cells.
Conclusion
Banf1 is a candidate marker of lung cancer patient prognosis with Banf1 depleted cells having altered sensitivity to cisplatin treatment. Understanding the mechanism by which Banf1 affects lung cancer cell sensitivity to this drug is an ongoing research process that may have major implications for lung cancer treatment. Identification of patient Banf1 expression levels may contribute to improved therapeutic tailoring while modulation of Banf1 expression may ultimately lead to significantly increased survival of diagnosed patients.
