Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib

Rosen, Ezra Y.; Johnson, Melissa L.; Clifford, Sarah; Somwar, Romel; Kherani, Jennifer; Son, Jieun; Bertram, Arrien A.; Davare, Monika A.; Gladstone, Eric; Ivanova, Elena; Henry, Dahlia; Kelley, Elaine M.; Lin, Mika; Milan, Marina S.D.; Nair, Binoj C.; Olek, Elizabeth; Scanlon, Jenna E.; Vojnic, Morana; Ebata, Kevin; Hechtman, Jaclyn F.; Li, Bob T.; Sholl, Lynette M.; Taylor, Barry S.; Ladanyi, Marc; Jänne, Pasi A.; Rothenberg, S. Michael; Drilon, Alexander; Oxnard, Geoffrey R.

doi:10.1158/1078-0432.ccr-20-2278

Cited by 98 publications

(76 citation statements)

References 26 publications

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“… 29 Another four cases of acquired selpercatinib resistance with MET amplification were reported and, it was demonstrated that this could be overcome by combining selpercatinib with crizotinib. 30 Given that >1000 patients with RET alterations were enrolled on selective RET inhibitor trials globally, these trials are still in progress, and the resistance mechanisms have been reported in just a few patients so far, the frequencies of various resistance mechanisms remain to be determined.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations

et al. 2021

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Background: Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes. Patients and methods: Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation. Results: RET G810C/S mutations at the solvent front and RET Y806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RET M918T/V804M/L , who initially responded to selpercatinib and developed resistance. RET G810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RETselpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft. Conclusions: RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.

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Section: Discussionmentioning

confidence: 99%

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations

et al. 2021

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“…Resistance to ALK TKIs consists of both on-target and off-target mechanisms. Off-target resistance mechanisms to 4G ALK TKIs will likely involve MET amplification which has been reported with the use of next-generation ALK or RET TKIs [42] , [43] , [44] , [45] , [46] . On-target resistance mechanisms such as single, double, or triple mutations are likely to be the most logical mechanism of resistance and will largely depend on the structures of TPX-0131 and NVL-655.…”

Section: Potential On-target Resistance To 4g Alk Tkismentioning

confidence: 99%

Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Nagasaka

Brazel

et al. 2021

Translational Oncology

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Highlights Concise yet comprehensive review of randomized phase 3 trials of ALK TKIs and approval timeline in the US. TPX-0131 and NVL-655 are 4th generation “double mutant active” ALK TKI as opposed to current 2nd and 3rd generation “single mutant active” ALK TKIs. Three randomized phase 3 designs are porposed for the development of these 4th generation ALK TKIs.

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“…For patients in which mutations in the RET kinase domain responsible for drug resistance were not detected, evidence exist mostly for the activation of bypass signaling pathways. MET dependence has been reported as a recurring and potentially targetable mechanism of resistance to selpercatinib and pralsetinib [81][82][83]. Preclinical studies have demonstrated that EGFR transduced bypass signals to critical downstream pathways which regulate cell proliferation and survival via ERK and AKT, enabling cancer cells to evade RET inhibitors.…”

Section: Reported Mechanisms Of Off-target Drug Resistancementioning

confidence: 99%

Diagnostics, therapeutics and RET inhibitor resistance for RET fusion–positive non-small cell lung cancers and future perspectives

Lu¹,

Zhou²

2021

Cancer Treatment Reviews

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Selective RET inhibitors is the current hot topic, making multikinase inhibitors a thing of the past. However, the limitation of various test approaches, coupled with lack of knowledge of acquired resistance mechanisms, and specific patient groups that bear special consideration, remains a challenge. Herein, we outline utility of various diagnostic techniques, provide evidence to guide management of RET-fusion-positive Non-Small Cell Lung Cancer (NSCLC) patients, including specific patient groups, such as EGFR-mutant NSCLC patients who acquired RET fusions after resisting EGFR TKIs, and offer a compendium of mechanisms of acquired resistance to RET targeted therapies. This review further provides a list of ongoing clinical trials and summarizes perspectives to guide future development of drugs and trials for this population.

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Overcoming MET-Dependent Resistance to Selective RET Inhibition in Patients with RET Fusion–Positive Lung Cancer by Combining Selpercatinib with Crizotinib

Cited by 98 publications

References 26 publications

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations

Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations

Will the clinical development of 4th-generation “double mutant active” ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC?

Diagnostics, therapeutics and RET inhibitor resistance for RET fusion–positive non-small cell lung cancers and future perspectives

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