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. 2017 Jan 1;23(1):204-213.
doi: 10.1158/1078-0432.CCR-15-1601. Epub 2016 Jul 1.

Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer

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Free PMC article

Identification of Existing Drugs That Effectively Target NTRK1 and ROS1 Rearrangements in Lung Cancer

Curtis R Chong et al. Clin Cancer Res. .
Free PMC article

Abstract

Purpose: Efforts to discover drugs that overcome resistance to targeted therapies in patients with rare oncogenic alterations, such as NTRK1 and ROS1 rearrangements, are complicated by the cost and protracted timeline of drug discovery.

Experimental design: In an effort to identify inhibitors of NTRK1 and ROS1, which are aberrantly activated in some patients with non-small cell lung cancer (NSCLC), we created and screened a library of existing targeted drugs against Ba/F3 cells transformed with these oncogenes.

Results: This screen identified the FDA-approved drug cabozantinib as a potent inhibitor of CD74-ROS1-transformed Ba/F3, including the crizotinib-resistant mutants G2032R and L2026M (IC50 = 9, 26, and 11 nmol/L, respectively). Cabozantinib inhibited CD74-ROS1-transformed Ba/F3 cells more potently than brigatinib (wild-type/G2032R/L2026M IC50 = 30/170/200 nmol/L, respectively), entrectinib (IC50 = 6/2,200/3,500 nmol/L), and PF-06463922 (IC50 = 1/270/2 nmol/L). Cabozantinib inhibited ROS1 autophosphorylation and downstream ERK activation in transformed Ba/F3 cells and in patient-derived tumor cell lines. The IGF-1R inhibitor BMS-536924 potently inhibited CD74-NTRK1-transformed compared with parental Ba/F3 cells (IC50 = 19 nmol/L vs. > 470 nmol/L). A patient with metastatic ROS1-rearranged NSCLC with progression on crizotinib was treated with cabozantinib and experienced a partial response.

Conclusions: While acquired resistance to targeted therapies is challenging, this study highlights that existing agents may be repurposed to overcome drug resistance and identifies cabozantinib as a promising treatment of ROS1-rearranged NSCLC after progression on crizotinib. Clin Cancer Res; 23(1); 204-13. ©2016 AACR.

Figures

Figure 1
Figure 1
A: Top inhibitors of Ba/F3 transformed with CD74-ROS1, color coded by clinical development status: FDA-approved (green), phase III (yellow), phase II (blue), phase I (purple), and preclinical (grey). B: Top inhibitors of Ba/F3 transformed with CD74-NTRK1, color coded by clinical development status: FDA-approved (green), phase III (yellow), phase II (blue), phase I (purple), and preclinical (grey).
Figure 2
Figure 2
A: Inhibition of Ba/F3 transformed with CD74-NTRK1 proliferation by BMS-536924 (red, formula image, IC50 = 28 nM), crizotinib (green, formula image, IC50 = 75 nM), lestaurtinib (CEP-701, blue, formula image, IC50 = 15 nM), and dovitinib (black, ●, IC50 = 69 nM) and of Ba/F3 parental cells by BMS-536924 (red, formula image, IC50 = 2.75 μM), crizotinib (green, formula image, IC50 = 15.4 μM), lestaurtinib (CEP-701, blue formula image, IC50 = 3.4 μM), and dovitinib (■, IC50 = 4.2 μM). B: Inhibition of NTRK1 autophosphorylation and downstream signaling in CD74-NTRK1-transformed NIH-3T3 cells. C: Inhibition of NTRK1 autophosphorylation in CUTO-3 tumor cells derived from a patient harboring an MPRIP-NTRK1 rearrangement. D: Inhibition of CUTO-3 cells by crizotinib (green, formula image, IC50 = 462 nM), lestaurtinib (CEP-701, blue, formula image, IC50 = 3.5 nM), BMS-536924 (red, formula image, IC50 = 34 nM), dovitinib (black, ●, IC50 = 170 nM). E: Phe589 is postulated to be the “gatekeeper” residue in the NTRK1 kinase active site, and is modeled using space filling representation. F: Mutation of the putative “gatekeeper” residue Phe589 to Val does not abrogate inhibition of TRK autophosphorylation at residues 490 and 674/675 for lestaurtinib or BMS-536924.
Figure 3
Figure 3
A: Inhibition of Ba/F3 transformed with CD74-ROS1 wildtype (red, formula image), G2032R (green, formula image), L2026M (blue, formula image), and Ba/F3 parental cells (black, ●). B: Effect of drugs on ROS1 autophosphorylation (pY2274) and downstream activation of ERK signaling. C: Inhibition of the HCC78 NSCLC cell line by brigatinib (blue, formula image, IC50 = 2.2 μM), cabozantinib (red, formula image, IC50 = 1.36 μM) crizotinib (green, formula image, IC50 = 1.6 μM), and foretinib (black, ●, IC50 = 0.46 μM); data for alectinib (IC50 = 0.75 μM), brigatinib (IC50 = 2.2 μM), ceritinib (IC50 = 0.53 μM), entrectinib (IC50 = 0.45 μM), and PF-06463922 (IC50 = > 10 μM) not shown. D: Inhibition of ROS signaling in HCC78 cells. E: Molecular modeling of cabozantinib into the active site of ROS1 kinase domain, with dashed lines indicating hydrogen bonds.
Figure 4
Figure 4
A and B Computed tomography (CT) of the chest prior to cabozantinib therapy demonstrated a dominant mass in the left upper lobe (B, black arrow), measuring 4.3 cm in the longest diameter with patchy opacities (A, arrowheads) and a 1.7 cm discrete nodule in the right lower lobe (B, white arrow). Note bilateral small pleural effusions. C and D: On a chest CT scan performed due to dyspnea 4 weeks after the initiation of cabozantinib therapy, the the dominant lesion and surrounding tumor burden in the left upper lobe has mostly resolved with minimal residual opacities (C), indicating marked response to therapy. The right lower lobe lesion has also decreased, measuring 1.4 cm (arrow, D). Bilateral segmental pulmonary emboli are also noted (not shown), accounting for the clinical symptoms.

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