Progress and challenges in RET-targeted cancer therapy

Hu, Xiu‐Qin; Khatri, Ujjwol; Shen, Tao; Wu, Jie

doi:10.1007/s11684-023-0985-y

Cited by 14 publications

(7 citation statements)

References 76 publications

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“…RET rearrangements are also common in colorectal tumors with microsatellite instability and Spitz melanomas. Occasional instances of RET rearrangements have been described in breast carcinomas, KRAS mutation-negative pancreatic cancers, and some other tumor types [37,59,60,[64][65][66]. Two RET inhibitors, selpercatinib and pralsetinib, are the standard treatment option for RET-driven thyroid carcinomas as well as for RET-rearranged non-small cell lung cancers [63,66].…”

Section: Ret Rearrangementsmentioning

confidence: 99%

“…Occasional instances of RET rearrangements have been described in breast carcinomas, KRAS mutation-negative pancreatic cancers, and some other tumor types [37,59,60,[64][65][66]. Two RET inhibitors, selpercatinib and pralsetinib, are the standard treatment option for RET-driven thyroid carcinomas as well as for RET-rearranged non-small cell lung cancers [63,66]. In addition, selpercatinib has already received an agnostic approval for all tumor types carrying RET fusion.…”

Section: Ret Rearrangementsmentioning

confidence: 99%

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Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Aleksakhina,

Ivantsov,

Imyanitov

2024

IJMS

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Many tumors have well-defined vulnerabilities, thus potentially allowing highly specific and effective treatment. There is a spectrum of actionable genetic alterations which are shared across various tumor types and, therefore, can be targeted by a given drug irrespective of tumor histology. Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. Multiple lines of evidence suggest that this histology-independent approach is also reasonable for tumors carrying ALK and ROS1 translocations, biallelic BRCA1/2 inactivation and/or homologous recombination deficiency (HRD), strong HER2 amplification/overexpression coupled with the absence of other MAPK pathway-activating mutations, etc. On the other hand, some well-known targets are not agnostic: for example, PD-L1 expression is predictive for the efficacy of PD-L1/PD1 inhibitors only in some but not all cancer types. Unfortunately, the individual probability of finding a druggable target in a given tumor is relatively low, even with the use of comprehensive next-generation sequencing (NGS) assays. Nevertheless, the rapidly growing utilization of NGS will significantly increase the number of patients with highly unusual or exceptionally rare tumor-target combinations. Clinical trials may provide only a framework for treatment attitudes, while the decisions for individual patients usually require case-by-case consideration of the probability of deriving benefit from agnostic versus standard therapy, drug availability, associated costs, and other circumstances. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

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Section: Ret Rearrangementsmentioning

confidence: 99%

Section: Ret Rearrangementsmentioning

confidence: 99%

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Aleksakhina,

Ivantsov,

Imyanitov

2024

IJMS

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“…Whereas RET-selective protein tyrosine kinase inhibitors selpercatinib and pralsetinib rendered high rates of responses in RET-altered cancers, less than 10% of patients achieved a complete response 8 – 16 . The presence of residual tumors in most patients with RET-altered cancer after selpercatinib or pralsetinib treatment requires long-term disease management.…”

Section: Introductionmentioning

confidence: 99%

“…On-target mechanism of resistance to selpercatinib occurs most often in the RET G810 solvent-front site. Several next-generation of RET inhibitors are in preclinical or clinical development to overcome RET G810 solvent-front mutations 15 , 16 , 24 . However, although RET solvent-front mutation is a well-defined mechanism of selpercatinib and pralsetinib resistance that can be addressed with new RET TKIs, the rates of selpercatinib- and pralsetinib-resistant RET mutations are believed to be relatively low and is reported to be around 10% in a small study cohort 19 .…”

Section: Introductionmentioning

confidence: 99%

Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer

Subbiah,

Gouda,

Iorgulescu

et al. 2024

npj Precis. Onc.

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Patients treated with RET protein tyrosine kinase inhibitors (TKIs) selpercatinib or pralsetinib develop RET TKI resistance by secondary RET mutations or alterative oncogenes, of which alterative oncogenes pose a greater challenge for disease management because of multiple potential mechanisms and the unclear tolerability of drug combinations. A patient with metastatic medullary thyroid carcinoma (MTC) harboring a RET activation loop D898_E901del mutation was treated with selpercatinib. Molecular alterations were monitored with tissue biopsies and cfDNA during the treatment. The selpercatinib-responsive MTC progressed with an acquired ETV6::NTRK3 fusion, which was controlled by selpercatinib plus the NTRK inhibitor larotrectinib. Subsequently, tumor progressed with an acquired EML4::ALK fusion. Combination of selpercatinib with the dual NTRK/ALK inhibitor entrectinib reduced the tumor burden, which was followed by appearance of NTRK3 solvent-front G623R mutation. Preclinical experiments validated selpercatinib plus larotrectinib or entrectinib inhibited RET/NTRK3 dependent cells, whereas selpercatinib plus entrectinib was necessary to inhibit cells with RET/NTRK3/ALK triple alterations or a mixture of cell population carrying these genetic alterations. Thus, RET-altered MTC adapted to selpercatinib and larotrectinib with acquisition of ETV6::NTRK3 and EML4::ALK oncogenes can be managed by combination of selpercatinib and entrectinib providing proof-of-concept of urgency of incorporating molecular profiling in real-time and personalized N-of-1 care transcending one-size-fits-all approach.

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“…In 2020, the two RET-selective inhibitors pralsetinib (BLU-667) and selpercatinib (LOXO-292) were approved by the FDA for the treatment of RET-driven or thyroid cancer (Figure ). − Although they represented a turning point in the targeted therapy for these malignancies (higher efficacy, selectivity, more favorable pharmacokinetic properties, and fewer off-target interactions compared with the aforementioned MKIs), the development of resistance due to RET point mutations (e.g., Gly 810 Arg/Ser/Cys/Val, Leu 730 Val/Iso, and Tyr 806 Cys/Asn) also began to occur early with these drugs. − …”

Section: Introductionmentioning

confidence: 99%

Design and Synthesis of Novel Thieno[3,2-c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells

La Monica,

Pizzolanti,

Baiamonte

et al. 2023

ACS Omega

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RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDIT online web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2- c ]quinolines 6a–e and 7a–e were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and in vitro evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds 6a–d as promising anticancer agents, with IC 50 values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by in silico predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC.

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Progress and challenges in RET-targeted cancer therapy

Cited by 14 publications

References 76 publications

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer

Design and Synthesis of Novel Thieno[3,2-c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells

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