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Foretinib Is a Potent Inhibitor of Oncogenic ROS1 Fusion Proteins

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Foretinib Is a Potent Inhibitor of Oncogenic ROS1 Fusion Proteins Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins Monika A. Davarea,1, Anna Saborowskib,1, Christopher A. Eidea,c, Cristina Tognona,c, Rebecca L. Smitha, Johannes Elferichd, Anupriya Agarwala, Jeffrey W. Tynera,e, Ujwal P. Shinded, Scott W. Loweb,c, and Brian J. Drukera,c,2 aKnight Cancer Institute, cHoward Hughes Medical Institute, and Departments of dBiochemistry and Molecular Biology and eCell and Developmental Biology, Oregon Health and Sciences University, Portland, OR 97239; and bMemorial Sloan-Kettering Cancer Center, New York, NY 10065 Contributed by Brian J. Druker, October 21, 2013 (sent for review June 24, 2013) The rapidly growing recognition of the role of oncogenic ROS1 early results appear promising, consistent with the clinical ex- fusion proteins in the malignant transformation of multiple cancers, perience of crizotinib in patients with ALK-positive lung cancer including lung adenocarcinoma, cholangiocarcinoma, and glioblas- to date, as well as prior experience with kinase inhibitors in many toma, is driving efforts to develop effective ROS1 inhibitors for use other malignancies (10–13), recent evidence suggests that a sub- as molecularly targeted therapy. Using a multidisciplinary approach set of patients with crizotinib-treated ROS1 fusion-positive may involving small molecule screening in combination with in vitro and acquire ROS1 kinase domain mutations that confer drug re- in vivo tumor models, we show that foretinib (GSK1363089) is sistance, thus necessitating alternative therapeutic approaches. a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ To identify additional and potentially more efficacious ROS1 ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demon- inhibitors, we used an unbiased, high-throughput kinase inhibitor strated promising early results in patients with ROS1-rearranged screening assay and discovered that foretinib (GSK1363089) and non–small-cell lung carcinoma, recently emerging clinical evidence Gö6976 are potent inhibitors of ROS1. Foretinib selectively suggests that patients may develop crizotinib resistance due to ac- suppresses the growth of the SLC–ROS-driven human NSCLC quired point mutations in the kinase domain of ROS1, thus neces- cell line HCC78 and of FIG–ROS-driven murine cholangi- sitating identification of additional potent ROS1 inhibitors for ocarcinoma, but not of EGFR-driven NSCLC or phosphatase therapeutic intervention. We confirm that the ROS1G2032R mutant, and tensin homolog (PTEN)-suppressed murine cholangio- recently reported in clinical resistance to crizotinib, retains foretinib carcinoma cells. Further, treatment of tumor-bearing mice sensitivity at concentrations below safe, clinically achievable levels. with foretinib resulted in specific and dramatic regression of Furthermore, we use an acceleratedmutagenesisscreentopre- FIG–ROS-driven tumors in contrast to non-FIG–ROS tumors emptively identify mutations in the ROS1 kinase domain that that share similar histopathological features. Importantly, we confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data also use a cell-based in vitro resistance screen to preemptively strongly suggest that foretinib is a highly effective ROS1 inhibi- identify several ROS1 kinase domain point mutations that tor, and further clinical investigation to evaluate its potential confer resistance to crizotinib and show that these crizotinib- therapeutic benefit for patients with ROS1-driven malignancies resistant ROS1 mutants remain sensitive to foretinib. These is warranted. datasuggestthatforetinibmayprovide an alternative front-line treatment for ROS1-positive tumors and an effective second-line eceptor tyrosine kinases (RTKs) are critical mediators of approach for patients that develop crizotinib-resistant disease. Rextracellular signals that control key cell growth, survival, and motility pathways. Conversely, deregulated and constitutive Significance RTK activation is responsible for the initiation and progression of many cancers. Multiple mechanisms contribute to aberrant ROS1 fusion kinases are critical oncogenes in several malig- RTK activation including chromosomal rearrangements, point nancies, suggesting that ROS1 inhibitors are likely to be effec- mutations, and gene amplification. Oncogenic activation of the tive molecularly targeted therapies in these patients. Although orphan RTK c-ros oncogene 1 (ROS1) is observed in a subset of phase I/II clinical trials using the ALK/ROS1 inhibitor crizotinib patients with glioblastoma, non–small-cell lung cancer (NSCLC), to treat ROS1 fusion-harboring non–small-cell lung cancer and cholangiocarcinoma (1–5). In most cases, ROS1 signaling is patients demonstrate early success, evidence of clinical re- activated by interchromosomal translocation or intrachromosomal sistance to crizotinib due to the acquired ROS1G2032R mutation deletion that results in N-terminal ROS1 fusion genes. Several was recently reported. Here, we demonstrate that foretinib is ROS1 kinase fusion proteins have been identified, including the a more potent ROS1 inhibitor than crizotinib in vitro and in Fused in Glioblastoma–ROS1 (FIG–ROS) that was first dis- vivo and remains effective against crizotinib-resistant ROS1 covered in a human glioblastoma cell line (2) and more recently kinase domain mutations, including ROS1 G2032R. Taken to- in patients with NSCLC (4), cholangiocarcinoma (3), and serous gether, our findings establish foretinib as a highly promising ovarian carcinoma (6). The SLC34A2–ROS1 (SLC–ROS) fusion therapeutic candidate for treating patients with ROS1-driven is present in a subset of patients with NSCLC (1, 7) and gastric malignancies and provide rationale for rapid clinical translation. cancer (8). Other ROS1 fusions include CD74–ROS1, EZR– ROS1, LRIG3–ROS1, SDC4–ROS1, and TPM3–ROS1 (5). Author contributions: M.A.D., A.S., C.A.E., C.T., U.P.S., S.W.L., and B.J.D. designed re- search; M.A.D., A.S., C.A.E., C.T., R.L.S., J.E., A.A., and U.P.S. performed research; M.A.D., Given the recent success of molecularly targeted therapies in A.S., C.T., J.E., A.A., J.W.T., U.P.S., and S.W.L. contributed new reagents/analytic tools; treating cancers driven by oncogenic kinases, there is acute M.A.D., A.S., C.T., R.L.S., and B.J.D. analyzed data; and M.A.D., A.S., C.A.E., C.T., J.E., J.W.T., clinical momentum to identify inhibitors that selectively target S.W.L., and B.J.D. wrote the paper. ROS1 fusions. Because the ROS1 and Anaplastic Lymphoma The authors declare no conflict of interest. Kinase (ALK) domains are partially homologous, the Food and 1M.A.D. and A.S. contributed equally to this work. Drug Administration (FDA)-approved ALK/MET kinase in- 2To whom correspondence should be addressed. E-mail: [email protected]. hibitor crizotinib is being investigated via phase I/II clinical trials This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. MEDICAL SCIENCES for its efficacy in ROS1-driven lung cancer patients (9). Although 1073/pnas.1319583110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1319583110 PNAS | November 26, 2013 | vol. 110 | no. 48 | 19519–19524 Downloaded by guest on September 30, 2021 Results crizotinib and the ALK inhibitor NVP–TAE684 (TAE684) have High-Throughput Kinase Inhibitor Screen Identifies Foretinib and recently been reported to show activity against ROS1 fusions Gö6976 as Potent ROS1 Inhibitors. The FIG–ROS fusion protein in Ba/F3 cells (3, 4) and in the SLC–ROS-expressing human transforms a murine interleukin-3 dependent pro-B lineage cell NSCLC cell line HCC78 (1, 7). Consistent with these published line, Ba/F3, and National Institutes of Health (NIH) 3T3 cells studies and providing validation of our screening approach, we and promotes tumor formation in vivo (3, 5). To identify ROS1 identified both crizotinib and TAE684 as inhibitors of Ba/F3 – inhibitors that selectively block the growth of Ba/F3 FIG–ROS FIG ROS cell growth, with IC50s of 38 nM and 2 nM, re- cells, we used a cell-based high-throughput kinase inhibitor spectively (Fig. 1 A and B). screen encompassing graded concentrations of 104 unique in- Given current efforts to treat ROS1-driven cancers with ALK hibitors seeded in 384-well plates (Dataset S1). The following inhibitors (14), we directly compared the efficacy of foretinib and criteria were used to select potential ROS1 inhibitors for further Gö6976 to the previously known ALK inhibitors, crizotinib, evaluation: selective sensitivity of the Ba/F3 FIG–ROS cells at an TAE684, and GSK1838705A (15). For this, we used Ba/F3 cells inhibitor concentration ≤10 nM and a ≥5-fold lower 50% growth expressing ROS1 fusions, the EML4–ALK fusion, or the acti- F1174L inhibitory constant (IC50) compared with Ba/F3 cells expressing vating ALK point mutant (16). To determine whether the BCR–ABL or Ba/F3 parental cells. Using this assay, we identi- targeting efficiency is comparable for different ROS1 fusions, we fied foretinib and Gö6976 as two potent inhibitors of Ba/F3 used Ba/F3 cells expressing either SLC–ROS or FIG–ROS. FIG–ROS cell growth with IC s of 2 nM and 1 nM, respectively Foretinib demonstrated potent inhibition of both the FIG–ROS 50 – (Fig. 1 A and B). Human ROS1 and ALK share 42–48% kinase and SLC ROS fusions (IC50: 2 nM and 10 nM, respectively), domain homology, and consequently the ALK/MET inhibitor representing ∼20-fold increased inhibitory potency compared with crizotinib (IC50: 38 nM and 220 nM, respectively). Ba/F3 cells expressing either EML4–ALK or ALKF1174L were relatively insensitive to foretinib and Gö6976 but robustly inhibited by the A D ALK-targeted compounds (Fig. 1B). In agreement with these 1.25 Ba/F3 FIG-ROS 1.25 HCC78 findings, foretinib and Gö6976 effectively induced apoptosis in Crizotinib 1.00 1.00 Crizotinib Ba/F3 FIG–ROS and SLC–ROS but not in EML4–ALK- or Foretinib Foretinib F1174L 0.75 Gö6976 0.75 ALK -expressing cells (Fig. S1 A–C). 0.50 TAE684 0.50 fi GSK1838705A Foretinib is a multikinase inhibitor with reported ef cacy for Cell Viability Cell Viability 0.25 0.25 fi MET and VEGFR2 (17).
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