Reference Detail

Ref Type

Journal Article

PMID

(32918045)

Authors

Xia ZJ, Ji YC, Sun DQ, Peng X, Gao YL, Fang YF, Zhao XD, Wang WB, Ding J, Geng MY, Ai J

Title

SAF-189s, a potent new-generation ROS1 inhibitor, is active against crizotinib-resistant ROS1 mutant-driven tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Acta pharmacologica Sinica	42	6	2021 Jun	998-1004	Acta Pharmacol Sin

URL

Abstract Text

The ROS1 fusion kinase is an attractive antitumor target. Though with significant clinical efficacy, the well-known first-generation ROS1 inhibitor (ROS1i) crizotinib inevitably developed acquired resistance due to secondary point mutations in the ROS1 kinase. Novel ROS1is effective against mutations conferring secondary crizotinib resistance, especially G2032R, are urgently needed. In the present study, we evaluated the antitumor efficacy of SAF-189s, the new-generation ROS1/ALK inhibitor, against ROS1 fusion wild-type and crizotinib-resistant mutants. We showed that SAF-189s potently inhibited ROS1 kinase and its known acquired clinically resistant mutants, including the highly resistant G2032R mutant. SAF-189s displayed subnanomolar to nanomolar IC50 values against ROS1 wild-type and mutant kinase activity and a selectivity vs. other 288 protein kinases tested. SAF-189s blocked cellular ROS1 signaling, and in turn potently inhibited the cell proliferation in HCC78 cells and BaF3 cells expressing ROS1 fusion wild-type and resistance mutants. In nude mice bearing BaF3/CD74-ROS1 or BaF3/CD74-ROS1G2032R xenografts, oral administration of SAF-189s dose dependently suppressed the growth of both ROS1 wild-type- and G2032R mutant-driven tumors. In a patient-derived xenograft model of SDC4-ROS1 fusion NSCLC, oral administration of SAF-189s (20 mg/kg every day) induced tumor regression and exhibited notable prolonged and durable efficacy. In addition, SAF-189s was more potent than crizotinib and comparable to lorlatinib, the most advanced ROS1i known against the ROS1G2032R. Collectively, these results suggest the promising potential of SAF-189s for the treatment of patients with the ROS1 fusion G2032R mutation who relapse on crizotinib. It is now recruiting both crizotinib-relapsed and naive ROS1-positive NSCLC patients in a multicenter phase II trial (ClinicalTrials.gov Identifier: NCT04237805).

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Foritinib	Foritinib	7	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Foritinib		Foritinib succinate\|SAF189s\|SAF 189s\|SAF-189s	ALK Inhibitor 32 ROS1 Inhibitor 20	Foritinib is an ALK and ROS1 inhibitor that is able to penetrate the central nervous system, which potentially reduces tumor cell proliferation and tumor growth (PMID: 32918045).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ROS1	L2026M	missense	unknown	ROS1 L2026M lies within the protein kinase domain of the Ros1 protein (UniProt.org). L2026M has been demonstrated to confer resistance to ROS1 inhibitors in the context of a Ros1 fusion (PMID: 25351743, PMID: 32918045), and results in increased colony formation, cell migration, and ERK/AKT signaling in the context of a ROS1 fusion in culture (PMID: 38148635), but has not been individually characterized and therefore, its effect on Ros1 protein function is unknown.	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ROS1 S1986F	Advanced Solid Tumor	predicted - sensitive	Lorlatinib	Preclinical - Biochemical	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited kinase activity of a transformed cell line expressing ROS1 S1986F in culture (PMID: 32918045).	32918045
ROS1 L2026M	Advanced Solid Tumor	predicted - sensitive	Lorlatinib	Preclinical - Biochemical	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited kinase activity of a transformed cell line expressing ROS1 L2026M in culture (PMID: 32918045).	32918045
ROS1 G2032R	Advanced Solid Tumor	predicted - sensitive	Lorlatinib	Preclinical - Biochemical	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited kinase activity of a transformed cell line expressing ROS1 G2032R in culture (PMID: 32918045).	32918045
ROS1 G2032R	Advanced Solid Tumor	predicted - resistant	Ceritinib	Preclinical - Biochemical	Actionable	In a preclinical study, Zykadia (ceritinib) treatment did not inhibit kinase activity of a transformed cell line expressing ROS1 G2032R in culture (PMID: 32918045).	32918045
ROS1 S1986Y	Advanced Solid Tumor	predicted - sensitive	Lorlatinib	Preclinical - Biochemical	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited kinase activity of a transformed cell line expressing ROS1 S1986Y in culture (PMID: 32918045).	32918045
ROS1 S1986Y	Advanced Solid Tumor	predicted - sensitive	Foritinib	Preclinical - Biochemical	Actionable	In a preclinical study, Foritinib inhibited kinase activity of a transformed cell line expressing ROS1 S1986Y in culture (PMID: 32918045).	32918045
ROS1 G2032R	Advanced Solid Tumor	predicted - sensitive	Foritinib	Preclinical - Biochemical	Actionable	In a preclinical study, Foritinib inhibited kinase activity of a transformed cell line expressing ROS1 G2032R in culture (PMID: 32918045).	32918045
ROS1 L2026M	Advanced Solid Tumor	predicted - sensitive	Foritinib	Preclinical - Biochemical	Actionable	In a preclinical study, Foritinib inhibited kinase activity of a transformed cell line expressing ROS1 L2026M in culture (PMID: 32918045).	32918045
ROS1 G2032R	Advanced Solid Tumor	predicted - resistant	Crizotinib	Preclinical - Biochemical	Actionable	In a preclinical study, Xalkori (crizotinib) treatment did not inhibit kinase activity of a transformed cell line expressing ROS1 G2032R in culture (PMID: 32918045).	32918045
ROS1 S1986F	Advanced Solid Tumor	predicted - sensitive	Foritinib	Preclinical - Biochemical	Actionable	In a preclinical study, Foritinib inhibited kinase activity of a transformed cell line expressing ROS1 S1986F in culture (PMID: 32918045).	32918045
ROS1 D2033N	Advanced Solid Tumor	predicted - sensitive	Lorlatinib	Preclinical - Biochemical	Actionable	In a preclinical study, Lorbrena (lorlatinib) inhibited kinase activity of a transformed cell line expressing ROS1 D2033N in culture (PMID: 32918045).	32918045
ROS1 D2033N	Advanced Solid Tumor	predicted - sensitive	Foritinib	Preclinical - Biochemical	Actionable	In a preclinical study, Foritinib inhibited the kinase activity of a transformed cell line expressing ROS1 D2033N in culture (PMID: 32918045).	32918045