1013P - Utilizing a combined biomarker and therapeutic strategy to reverse TKI resistance in EGFR mutant non-small cell lung cancer

Background

Tyrosine kinase inhibitors (TKIs) are first-line therapy for non-small-cell lung cancers (NSCLC) that harbor sensitizing mutations within the epidermal growth factor receptor (EGFR). However, resistance to TKIs such as Osimertinib remain a primary issue. Herein, we have identified the protein cell division cycle associated protein-3 (CDCA3) as a potential biomarker for TKI sensitivity and a unique therapeutic approach to target TKI resistance.

Methods

We combined the screening of multiple models of TKI resistance (H1975 (T790M+) and isogenic parental and resistant HCC827, H3255, PC-9 cell lines) with systems biology profiling of our quantitative SWATH proteomics and publicly available TCGA RNA-seq data. A tissue-microarray of 150 tumors and panel of 13 NSCLC adenocarcinoma cell line panel were screened.

Results

We demonstrate that in our expanded tissue microarray cohort of EGFR mutant tumors that CDCA3 protein are markedly elevated in EGFR mutant NSCLC and prognostic. Consistently, low CDCA3 expression (H-score < median) correlated with emergence of TKI resistance (p < 0.01) and in a panel of EGFRmut cell lines, CDCA3^low cell lines demonstrated significantly reduced potency for erlotinib and Osimertinib (p = 0.018). In explant models, we demonstrate that the casein kinase-2 (CK2) inhibitor CX-4945 induces upregulation of CDCA3 protein. Our prior work demonstrated that CDCA3 protein turnover is controlled in a CK2-dependent manner. Consistently, CX-4945 upregulated CDCA3 levels in TKI insensitive and resistant EGFRmut NSCLC cell lines. CX-4945 also significantly enhanced the potency of Osimertinib in isogenic models of acquired resistance (p > 0.001).

Conclusions

Our findings demonstrate a combined biomarker and therapeutic strategy for EGFR mutant NSCLC. CK2 blockade to upregulate CDCA3, especially prior to development of therapy resistance and in CDCA3^low settings, might benefit people living with EGFR mutant NSCLC by improving the response to EGFR TKIs. Given our published work demonstrating CDCA3 as a biomarker for platinum-based chemotherapy response in NSCLC without EGFR mutations, our biomarker may also have utility to enhance the effectiveness of chemoimmunotherapy in EGFR mutant tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Cancer Australia.

Disclosure

All authors have declared no conflicts of interest.