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Ref Type | Abstract | ||||||||||||
PMID | |||||||||||||
Authors | Alexander E. Drilon, Dayong Zhai, Evan Rogers, Wei Deng, Xin Zhang, Jane Ung, Dong Lee, Laura Rodon, Armin Graber, Zachary Franklin Zimmerman, Brion W Murray, Vivek Subbiah | ||||||||||||
Title | The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models. | ||||||||||||
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URL | https://ascopubs.org/doi/abs/10.1200/JCO.2020.38.15_suppl.3616 | ||||||||||||
Abstract Text | RET fusions/mutations drive oncogenesis in lung and thyroid cancers, and several other malignancies. Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. On-target resistance includes the acquisition of solvent front mutations (SFMs i.e. RET G810 substitutions). TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations including SFMs. Methods: The rationally-designed, compact, macrocyclic RET/SRC inhibitor TPX-0046 was characterized in RET-driven in vitro and in vivo tumor models. Results: In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. It was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 < 10 nM) in tumor cell lines (LC2/ad, CCDC6-RET; TT, RET C634W) and Ba/F3 engineered RET models (WT, G810R). In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values ~1 nM. Ba/F3 RET engineered cells with SFMs (e.g. G810C/R/S) were potently inhibited by TPX-0046 (mean proliferation IC50 1–17 nM). TPX-0046 demonstrated marked in vivo anti-tumor efficacy in RET-driven cell-derived and patient-derived xenograft tumor models. In a Ba/F3 KIF5B-RET xenograft model, a single dose of 5 mg/kg TPX-0046 inhibited > 80% of RET phosphorylation (corresponding mean free plasma concentration: 51 nM). At 5 mg/kg BID, tumor regression was observed in RET-dependent xenograft models, including those that harbor RET SFMs: TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R. Conclusions: TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391). |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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RET G810R | Advanced Solid Tumor | predicted - sensitive | TPX-0046 | Preclinical - Cell culture | Actionable | In a preclinical study, TPX-0046 treatment led to inhibition of cell proliferation in a transformed cell line expressing RET G810R in culture (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 3616-3616). | detail... |
RET G810S | Advanced Solid Tumor | predicted - sensitive | TPX-0046 | Preclinical - Cell culture | Actionable | In a preclinical study, TPX-0046 treatment led to inhibition of cell proliferation in a transformed cell line expressing RET G810S in culture (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 3616-3616). | detail... |
RET G810C | Advanced Solid Tumor | predicted - sensitive | TPX-0046 | Preclinical - Cell culture | Actionable | In a preclinical study, TPX-0046 treatment led to inhibition of cell proliferation in a transformed cell line expressing RET G810C in culture (J Clin Oncol 38, no. 15_suppl (May 20, 2020) 3616-3616). | detail... |