Targeting Fact Complex With Cbl0137 To Overcome Acquired Resistance To Egfr-Tki In Lung Adenocarcinoma

Multiple randomized clinical trials have demonstrated that first line treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) such as afatinib in lung adenocarcinoma patients with EGFR mutations results in better progression free survival, response and quality of life, compared to chemotherapy. Despite excellent initial responses, almost all patients eventually acquire resistance to EGFR-TKI and overall survival for these patients remains dismal. Acquired resistance to EGFR-TKI results from several distinct mechanisms, including second site mutations (such as T790M), Met amplification and NFκB activation. An evolving hypothesis is that most patients achieve an initial incomplete response to EGFR-TKI but have residual disease comprised of cells that have developed an adaptive survival response to EGFR inhibition. Activation of NFkB and acquisition of stem cell like properties are important for this adaptive response. CBL0137 is a curaxin that inhibits NFκB and targets cancer stem cells preferentially by causing chromatin trapping of the FACT (facilitates chromatin transcription) complex. We evaluated the combination of CBL0137 and afatinib in EGFR mutant cell lines and a patient-derived xenograft (PDX) with acquired resistance to EGFR TKI. Drug synergy experiments were done in the EGFR mutant lung adenocarcinoma cell lines H1975 and H1993 with acquired resistance due to T790M and Met amplification, respectively. Cell viability was measured by MTT assay and synergy was quantified by using ChouTalalay combination indices (CI). The PDX was obtained from a patient with an EGFR mutation and progression after treatment with erlotinib with no detectable T790M mutation. To evaluate the efficacy of the afatinib-CBL0137 combination in mice bearing PDX tumors, afatinib (5 mg/kg orally/days 1-5 every week) alone, CBL0137 (50 or 75 mg/kg IV/once a week) alone, a combination of afatinib and CBL0137, or vehicle alone were administered for 52 days and tumor growth was measured every other day. Ten mice were used for each test. In the cell lines, the combination of afatinib and CBL0137 was synergistic with CI less than 1. The combination of afatinib and CBL0137 was well tolerated in the mice. In the treatment groups of vehicle alone, afatinib alone, CBL0137 50 mg/kg alone or 75 mg/kg alone, tumor volumes increased by factors of ∼35, 17.5, 17.5 and 12.5, respectively. There was no significant tumor growth for 3 weeks in mice treated with the combination of afatinib and CBL0137. After 3 weeks of treatment, the tumors started to grow slowly and increased in volume approximately 5 fold by day 52 when the treatment was stopped. We conclude that the combination of CBL0137 and afatinib is synergistic and can overcome acquired resistance to an EGFR TKI in an EGFR mutant lung adenocarcinoma. Phase I oral and IV clinical trials of CBL0137 monotherapy in solid tumors are ongoing, and combination studies with afatinib are being planned. Citation Format: Neelesh Sharma, Josephine Dermawan, Andrei Purmal, Daniel Lindner, Gary Wildey, Afshin Dowlati, Andrei Gudkov, Katerina Gurova, George R. Stark. Targeting FACT complex with CBL0137 to overcome acquired resistance to EGFR-TKI in lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3036.