Stem-Like Colorectal Cancer Cell Lines Show Response To The Erk1/2 Inhibitor, Sch772984, Alone And In Combination With Neratinib

Background: We have recently shown an association of colorectal tumor subtypes with differential response to chemotherapy in patients (pts), and to targeted therapy in cell lines. Pts enrolled in NSABP/NRG C-07 with stem-like tumors had a poor prognosis regardless of stage or treatment, highlighting the importance of finding new treatments for stem-like tumors. Our in-vitro data showed that KRAS mutant (mt) cell lines of the intrinsic inflammatory subtype were sensitive to the combination of MEK-162 and neratinib, but stem-like subtype cell lines were resistant regardless of KRAS mt status. The purpose of this study was to extend our observations to xenograft models and to identify new agents that target the stem-like subtype. Methods: KRAS mt cell lines of the inflammatory (NCI-H747) or stem-like (SW-480) subtype were used in xenograft models to test inhibition of tumor growth by MEK-162 and neratinib, alone or in combination. Five stem-like cell lines with KRAS wt (C2BBE1, HS675T) or KRAS mt (SW480, SW620, HCT116), and two KRAS mt inflammatory cell lines (NCI-H747, SW837) were tested for cell viability after treatment with SCH772984 alone or in combination with neratinib. Results: In vivo analysis showed that treatment of NCI-H747 xenografts with a combination of MEK-162 (3mg/kg) and neratinib (10mg/kg) led to significant tumor regression compared to treatment with either drug alone (p ≥0.0001 v neratinib alone; p ≥0.002 v MEK-162 alone). In contrast, MEK-162 alone was able to inhibit tumor growth of stem-like cell line (SW480) xenografts (p ≥0.0061 v control) but neratinib was ineffective (p ≥0.145 v control) as a single agent and did not add to MEK-162. Our in-vitro and in-vivo data showed that inhibition of p-ERK directly correlated with sensitivity to the MEK and neratinib combination in inflammatory subtype. SCH772984 significantly inhibited cell viability of both inflammatory (IC50 1-2 μM) and stem-like subtype (IC50 1-2 μM) cell lines. The combination of neratinib (0.125 μM) and SCH772984 (1 μM) was effective at decreasing cell viability by 60-70% in both inflammatory and stem-like cell lines. Inhibition of ERK phosphorylation was correlated with loss of cell viability. Conclusion: The combination of MEK-162 and neratinib work synergistically to decrease tumor growth in inflammatory but not stem-like colorectal cancer subtypes. We demonstrate that SCH772984 decreases the viability of stem-like colon cancer cell lines, and works synergistically with neratinib. The use of SCH772984 alone, but more potently in combination with neratinib, may represent a therapeutic approach for pts with stem-like tumors, a finding that underscores the potential importance of employing subtype analysis in the diagnosis of colon cancer and potentially as to a guide to new therapies. Support: PA DoH, which disclaims certain responsibility. Citation Format: Rekha Pal, Ning Wei, Nan Song, Shao-yu Wu, S. Rim Kim, Patrick G. Gavin, Peter C. Lucas, Ashok Srinivasan, Samuel A. Jacobs, Soonmyung Paik, John C. Schmitz, Kay Pogue-Geile. Stem-like colorectal cancer cell lines show response to the ERK1/2 inhibitor, SCH772984, alone and in combination with neratinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5167. doi:10.1158/1538-7445.AM2017-5167