TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers

Drilon, Alexander; Rogers, Evan; Zhai, Dayong; Deng, Wei; Zhang, X.; Lee, D.; Ung, Jane; Whitten, Jeffrey P.; Zhang, H.; Liu, J.; Hu, Tingsong; Zhuang, Hao; Lu, Yuelie; Huang, Zhiqing; Graber, Armin; Zimmerman, Zach; Xin, Rui; Cui, Jingru; Subbiah, Vivek

doi:10.1093/annonc/mdz244.068

Cited by 48 publications

(45 citation statements)

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“…Although the true frequency of acquired RET solvent front mutations remains to be established, their identification (unaccompanied by recurrent alterations in other genes) in five patients with different tumor histologic diagnoses (NSCLC or MTC) and different founder RET alterations (fusions or mutations), and the identification of multiple distinct clonal event resulting in mutations involving G810 present at multiple sites of metastatic disease in the same patient suggest that the development of potent inhibitor of these mutations could be an effective strategy to target resistance to selective RET inhibitors. One recently described MKI (TPX-0046) inhibits RET solvent front mutations (and other non-RET kinases, including SRC) preclinically but lacks inhibitory activity against RET gatekeeper mutations; 26 however, as shown here, selective inhibition of both mutations may be important for patients. Current efforts are focused on the development of a next-generation selective RET TKI capable of inhibiting RET solvent front and gatekeeper mutations simultaneously.…”

Section: Discussionmentioning

confidence: 72%

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

Solomon

Tan

Lin

et al. 2020

Journal of Thoracic Oncology

220

160

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Section: Discussionmentioning

confidence: 72%

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

Solomon

Tan

Lin

et al. 2020

Journal of Thoracic Oncology

220

160

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“…phosphorylation, of SRC and EGFR/FGFR ( Das and Cagan, 2017 ). Accordingly, a phase 1/2 clinical study of the multi-targeted RET and SRC kinase inhibitor TPX-0046 (NCT04161391), is ongoing for TKI-naive and TKI-pretreated patients with RET-altered lung, thyroid and other cancers ( Drilon et al, 2019c ).…”

Section: Discussionmentioning

confidence: 99%

RET inhibition in novel patient-derived models of RET fusion- positive lung adenocarcinoma reveals a role for MYC upregulation

Hayashi

Odintsov

Smith

et al. 2021

Disease Models &Amp; Mechanisms

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Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET-fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5’ fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and down-regulated by cabozantinib treatment, opening up potentially new therapeutic avenues for combinatorial targeting RET-fusion driven lung cancers. The novel RET fusion-dependent preclinical models described herein represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.

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“…In preclinical studies, the novel and potent RET/SRC inhibitor TPX-0046 demonstrated remarkable activity against the solvent front mutation KIF5B-RET G810R, developed as on-target resistance to selpercatinib and pralsetinib. TPX-0046 is a selective next-generation RET/SRC inhibitor, that was rationally designed with a novel macrocyclic structure and developed against various RET mutations, especially solvent front mutations [ 138 ]. BOS172738 is another novel RET inhibitor with nanomolar potency against RET and approximately 300-fold selectivity against VEGFR2 and it is currently being studied in a phase I trial (NCT03780517) [ 139 ].…”

Section: Combination Strategies and Future Perspectivesmentioning

confidence: 99%

Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives

Fancelli

Caliman

Mazzoni

et al. 2021

Cancers

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The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.

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TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers

Cited by 48 publications

References 0 publications

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

RET Solvent Front Mutations Mediate Acquired Resistance to Selective RET Inhibition in RET-Driven Malignancies

RET inhibition in novel patient-derived models of RET fusion- positive lung adenocarcinoma reveals a role for MYC upregulation

Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives

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