Adaptive Darwinian off-target resistance mechanisms to selective RET inhibition in RET driven cancer
Vivek Subbiah1,2, Mohamed A Gouda3, J Bryan Iorgulescu4
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Vivek.Subbiah@scri.com.
Abstract:
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.
Insights
Resistance to RET tyrosine kinase inhibitors (TKIs) in medullary thyroid cancer can be overcome with combination therapies. Targeting acquired NTRK and ALK fusions alongside RET mutations offers a personalized treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Resistance to RET tyrosine kinase inhibitors (TKIs) like selpercatinib and pralsetinib in metastatic medullary thyroid carcinoma (MTC) is a significant clinical challenge.
- Acquired alternative oncogenes, rather than secondary RET mutations, represent a more complex mechanism of resistance.
- Understanding resistance mechanisms is crucial for developing effective therapeutic strategies in advanced MTC.
Purpose of the Study:
- To investigate the treatment response and resistance mechanisms in a patient with metastatic MTC harboring a RET activation loop mutation.
- To evaluate the efficacy of combination therapies targeting RET, NTRK, and ALK alterations.
- To demonstrate the utility of real-time molecular profiling for personalized cancer care.
Main Methods:
- Longitudinal monitoring of molecular alterations using tissue biopsies and circulating cell-free DNA (cfDNA).
- Treatment with selpercatinib, followed by combination therapy with larotrectinib and subsequently entrectinib.
- Preclinical validation of drug efficacy against specific genetic alterations.
Main Results:
- The patient initially responded to selpercatinib but developed acquired ETV6::NTRK3 fusion, which was controlled by adding larotrectinib.
- Subsequent progression with an EML4::ALK fusion was managed by combining selpercatinib with entrectinib.
- Preclinical models confirmed that selpercatinib plus entrectinib was effective against triple RET/NTRK3/ALK alterations.
Conclusions:
- Acquired ETV6::NTRK3 and EML4::ALK fusions can drive resistance to RET TKIs in MTC.
- Combination therapy with selpercatinib and entrectinib can overcome resistance mediated by multiple oncogenic fusions.
- Real-time molecular profiling and personalized N-of-1 care are essential for managing adaptive resistance in cancer.
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