Abstract 3783: Effective MEK inhibitor combinations to target tumor heterogeneity in <i>EGFR</i> mutant transformed SCLC
Authors: Atsuko Ogino, Xinmeng Jasmine Mu, Mika Lin, Antonio Calles, Stephen Wang, Man Xu, Lynette M. Scholl, Geoffrey R. Oxnard, Paul Kirschmeier, Pasi A. Jänne
Journal: Cancer Research (2019)

Abstract Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for the treatment of EGFR-mutant non-small lung cancer (NSCLC). In almost all cases, however, the response duration is limited and resistance ultimately emerges. Transformation of NSCLC to small cell lung cancer (SCLC) occurs as one of the resistance mechanisms to EGFR-TKIs. To date, the mechanism associated with this transformation is largely unknown, necessitating the need to establish an effective treatment strategy for patients with transformed SCLC (tSCLC). Methods: We isolated cancer cells that grow as floating aggregates (F) and adherent monolayers (Ad) from the pleural effusion of three patients with tSCLC to establish patient derived cell lines (DFCI112F, DFI112ad, DFCI190F, DFCI190ad, DFCI283F, DFCI283ad). In parallel, patient derived xenograft (PDX) models from these patients were successfully established by subcutaneous implantation of pleural effusions in NSG mice. Transcriptomic and genomic characterization of the cell lines were performed using whole-exome sequencing (WES) and RNA sequencing. These cell lines were further treated with a panel of agents, to screen for effective combination therapies. Results: Biological characterization of the created cell lines revealed that the floating aggregates have neuroendocrine (NE) features, while the adherent cell population presents non-NE/mesenchymal characteristics. The histology of the PDX tumors was confirmed as SCLC. According to WES, all tSCLC cell lines retained the original activating EGFR mutations. RB1 and TP53 were universally inactivated. Co-culturing the floating-NE cells with the adherent non-NE cells promoted the proliferation of the floating-NE cells in vitro. NE cells (DFCI112F) and non-NE cells (DFCI112ad) were injected into nude mice either as single or admixed populations. Tumor growth was observed only in admixed cell populations. In an effort to target both NE and non-NE populations, we performed a drug screen and demonstrated that MEK inhibitors are selectively efficacious against non-NE populations. We further evaluated the MEK inhibitor combination therapies with agents targeting NE populations (cisplatin, ABT-263 and JQ1), which effectively eliminated both NE and non-NE components in vitro. Our further study demonstrated that ABT-263 in combination with MEK inhibitors presented a synergistic effect, which could be a promising therapeutic combination for tSCLC patients. Conclusion: We demonstrate that the cancer cell lines established from tSCLC patients consist of heterogeneous population of cells with NE and non-NE/mesenchymal characteristics. The crosstalk between these two cell populations is observed and our findings underscore the importance of targeting tumor heterogeneity as a promising treatment strategy for patients with tSCLC. Citation Format: Atsuko Ogino, Xinmeng Jasmine Mu, Mika Lin, Antonio Calles, Stephen Wang, Man Xu, Lynette M. Scholl, Geoffrey R. Oxnard, Paul Kirschmeier, Pasi A. Jänne. Effective MEK inhibitor combinations to target tumor heterogeneity in EGFR mutant transformed SCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3783.