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|Authors||Hongying Zhang, Andrea Local, Jeffrey W. Tyner, Stephen E. Kurtz, Beth Wilmot, Shannon Mcweeney, Brian J. Druker, Stephen B. Howell, William G. Rice|
|Title||CG-806, a pan-FLT3 / pan-BTK inhibitor, demonstrates superior potency against cells from IDH-1 mutant and other non-favorable risk groups of AML patients.|
|Journal||Proceedings of the American Association for Cancer Research|
|Abstract Text||CG-806 is a pan-FLT3 / pan-BTK inhibitor that is more potent (IC50 = 0.08 µM, n=265, p < 0.001) than other FLT3 inhibitors including midostaurin, sorafenib, sunitinib, dovitinib, quizartinib, crenolanib and gilteritinib against acute myeloid leukemia (AML) primary patient samples containing wild-type or mutated FLT3. CG-806 has significant activity against AML cell lines with or without FLT3 internal tandem duplication (ITD) / tyrosine kinase domain (TKD) mutations and in mouse AML xenograft models. Oral CG-806 has a desirable safety profile in the pre-IND studies of rodent and dog 28-day GLP toxicology, rodent respiratory and central nervous system safety, and the bacterial reverse mutation assay. The current study explored the relationship between genetic abnormalities in bone marrow and peripheral mononuclear cells isolated from AML patients and sensitivity to CG-806 using an ex vivo cytotoxicity assay. To correlate CG-806 sensitivity with clinical status, gene abnormalities and expression levels, whole exome sequencing (n=118) and RNA sequencing (n=111) were performed. CG-806 was equally potent against cells from patients in the adverse, intermediate and favorable risk groups (2017 ELN risk stratification), and cells from patients with relapsed or transformed AML (WHO classification) were as sensitive as those from patients with de novo AML. CG-806 had equivalent potency in cases of TP53 WT and TP53 mutations, whereas cases with TP53 mutations were resistant (FDR-corrected p<0.1) to most other FLT3 inhibitors including midostaurin, sorafenib, sunitinib, dovitinib, quizartinib and crenolanib. CG-806 had similar potency in cases with ASXL1 or SRSF2 mutations compared to WT, whereas sunitinib and crenolanib appeared resistant to ASXL1 and SRSF2 mutations, respectively. As expected, patient samples with FLT3-ITD mutation were more sensitive to CG-806 as compared to FLT3 WT (FDR-corrected p<0.01); in addition, cases with high ITD allelic ratio, including concurrent mutations with NPM1 and DNMT3A, had greater sensitivity than cases with low allelic ratio. Most unexpectedly, all 6 specimens containing IDH1 R132 mutations demonstrated significantly greater sensitivity to CG-806 relative to WT (FDR-corrected p<0.01), yet there was no increased sensitivity of IDH-2 mutant cells to CG-806. In conclusion, CG-806 demonstrated potency in primary AML patient samples across all AML subgroups including relapsed/refractory/transformed AML and those with genetic abnormalities related to poor prognosis. While patient samples with FLT3-ITD mutations were expected to have greater sensitivity to CG-806, the most surprising correlation was the sensitivity of patient samples with IDH1 R132 mutations. These features of CG-806 warrant investigation in the clinical setting.|
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|TP53 mutant||acute myeloid leukemia||predicted - sensitive||CG-806||Preclinical - Patient cell culture||Actionable||In a preclinical study, patient-derived acute myeloid leukemia cells harboring TP53 mutations were sensitive to CG-806 in culture (Proceedings of the American Association for Cancer Research, Vol 60, Mar 2019, Abstract #1323).||detail...|
|IDH1 R132X||acute myeloid leukemia||predicted - sensitive||CG-806||Preclinical - Patient cell culture||Actionable||In a preclinical study, patient-derived acute myeloid leukemia cells harboring IDH1 R132X mutations demonstrated increased sensitivity to CG-806 compared to wild-type cells in culture (Proceedings of the American Association for Cancer Research, Vol 60, Mar 2019, Abstract #1323).||detail...|