Abstract 3633
Background
Aurora Kinases (AURK) regulate mitosis and are often upregulated in cancer. SCLC is characterized by TP53 and RB1 loss and frequent MYC amplification. Our group, and others, have proved that MYC-driven SCLC are vulnerable to AURKA-inhibitors (AURKAi), but their use is limited by toxicity due to high AURKA expression. AURKB levels are variable in SCLC, making AURKB an attractive targeted therapeutic approach. A novel AURKBi, AZD2811NP (nanoparticle), is now being investigated in relapsed SCLC patients (NCT02579226). We hypothesize that molecularly defined subsets may be sensitive to AZD2811.
Methods
We tested 50 human-derived SCLC cell lines with AZD2811 in 96 hour proliferation assays. To identify translatable biomarkers of response, we correlated IC50 values with genomic (WES), transcriptomic (RNASeq), and proteomic profiling (RPPA).
Results
AZD2811 is active in a subset of SCLC cells: 13/30 (26%) have high sensitivity (IC50<30 nM, Cmax) and 7/30 (14%) intermediate (IC50=30-100nM). Comparing protein expression, we found that cMYC (Fold change, FC:2.5; P = 0.015) and Vimentin (FC:1.66; P = 0.022) were top biomarkers of sensitivity, while high E-cadherin (FC:1.94; P = 0.046) and BCL-2 (FC:1.86; P = 0.032) associated with resistance. Interestingly, among the 13 highly sensitive cells, only 5 overexpress cMYC, highlighting that activity of AURKBi is not limited to MYC-driven SCLC. Indeed, among recently-described transcription factor defined subsets of SCLC, a majority of the NEUROD1-defined subset (cMYC enriched) were sensitive to AZD2811, as 25% of ASCL1- and 67% of POU2F-3-defined ones. These data suggest that the ASCL1 subset includes heterogeneous sub-groups that require further analysis to dissect their molecular features. Mutations in EP300, a Histone acetyltransferase that controls chromatin modification and transcription, also predict sensitivity.
Conclusions
Our results show encouraging single agent in vitro activity of AZD2811 in SCLC cells, and suggest a novel biomarker-driven approach for combinations. Candidate biomarkers will be tested in samples from the ongoing clinical trial. The high BCL2 levels observed in resistant cells provide a rationale for exploring AURKB/BCL2-i combinations.
Clinical trial identification
NCT02579226.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
AstraZeneca.
Disclosure
C.A. Adelman: Full / Part-time employment: AstraZeneca. J. Travers: Full / Part-time employment: AstraZeneca. J. Heymach: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Licensing / Royalties: BioTree; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Genentech; Advisory / Consultancy: GSK; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Hengrui; Advisory / Consultancy: Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self), Licensing / Royalties: Spectrum; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Synta; Research grant / Funding (self): Bayer; Research grant / Funding (self): GlaxoSmithKline. L.A. Byers: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): GenMab; Advisory / Consultancy: BergenBio; Advisory / Consultancy: Pharma Mar; Advisory / Consultancy: SA; Advisory / Consultancy, Research grant / Funding (self): Sierra Oncology; Research grant / Funding (self): Tolero Pharmaceuticals. All other authors have declared no conflicts of interest.
Resources from the same session
5011 - LCSCAF1 maintains cancer stem-like traits by stabilizing c-Myc protein and promotes metastasis and recurrence in lung cancer
Presenter: Tao Guo
Session: Poster Display session 1
Resources:
Abstract
4955 - XAF1 Enhances Temozolomide Induced Autophagic Cell Death through AMPK signaling pathway
Presenter: Mingoo Lee
Session: Poster Display session 1
Resources:
Abstract
5616 - The effect of cortisol on methylation patterns in breast cancer cell lines
Presenter: Haya Intabli
Session: Poster Display session 1
Resources:
Abstract
4649 - Global and sex-specific epigenome-wide association studies for the identification of the main methylated loci related to smoking in a Mediterranean population
Presenter: Judith Begona Ramirez Sabio
Session: Poster Display session 1
Resources:
Abstract
4984 - Whole transcriptomics analyses of mimicking Circulating Tumor Cells (CTCs) by single-cell RNA sequencing (scRNAseq)
Presenter: Jessica Garcia
Session: Poster Display session 1
Resources:
Abstract
5926 - Comparison of enzymatic- and bisulfite conversion to map the plasma cell-free methylome in cancer
Presenter: Nicole Lambert
Session: Poster Display session 1
Resources:
Abstract
5454 - Detection of low mutations in hepatocellular carcinoma by using circulating tumor DNA
Presenter: Esl Kim
Session: Poster Display session 1
Resources:
Abstract
4428 - Variants in the JAK1 and JAK2 genes in the risk and prognosis of patients with cutaneous melanoma
Presenter: Bruna Carvalho
Session: Poster Display session 1
Resources:
Abstract
4409 - P-Rex1 expression in breast cancer patients.
Presenter: Angela Lara Montero
Session: Poster Display session 1
Resources:
Abstract
4185 - Modulation of Risk of Cutaneous Melanoma Patients by Variants in STAT3 Gene and Functional Analysis
Presenter: Gabriela Gomez
Session: Poster Display session 1
Resources:
Abstract