Emergence and Targeting of Acquired and Hereditary Resistance to Multikinase RET Inhibition in Patients With RET-Altered Cancer

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

“…Although there have been single-case reports of RET V804M and RET S904F mutations conferring resistance to the MKI vandetanib in patients, 18,19 and we recently reported the ability of selpercatinib to overcome both hereditary and acquired RET V804M gatekeeper mutation in patients, 17,18 this report of G810 solvent front mutations provides the first description of acquired, "ontarget" resistance to selective RET inhibition in patients (previous studies have identified RET solvent front mutations in preclinical models of resistance to MKIs, [22][23][24] but not in patients and not with selective RET TKIs). A limitation of this study is the relatively small cohort of patients with acquired resistance studied, and it is likely that activation of bypass signaling and other mechanisms of resistance to selective RET TKIs will be identified through analyses of additional progression biopsies.…”

“… 15 , 16 Although rare, RET mutation-mediated resistance to MKIs has been previously reported in single patients (e.g., RET V804M gatekeeper mutations and RET S904F), mechanisms underlying resistance to selective RET TKIs remain unknown. 17 - 20 Understanding these mechanisms is critical to enable the design of next-generation therapies that can overcome resistance.…”

Activity of the Highly Specific RET Inhibitor Selpercatinib (LOXO-292) in Pediatric Patients With Tumors Harboring RET Gene Alterations

“…Selpercatinib (LOXO-292) is a potent, adenosine triphosphate–competitive, highly selective small molecule RET inhibitor with nanomolar potency against diverse RET alterations (including anticipated acquired gatekeeper resistance mutations). 18 , 19 Preliminary results for selpercatinib in a phase I/II trial (LIBRETTO-001; ClinicalTrials.gov identifier: NCT03157128 ) are highly encouraging, showing that it is generally well tolerated and has marked antitumor activity in adolescent and adult patients with RET -altered cancers, including those with brain metastases and those with tumors resistant to previous multitargeted kinase inhibitors. 20 , 21 We report the clinical activity of selpercatinib in five pediatric patients with tumors harboring RET alterations, four of whom were ineligible for the selpercatinib clinical trial open at the time their treatment was started because of their young age (younger than 12 years).…”

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

“…Preclinically, V804M/L mutant models resulted in pan-resistance to several MKI, such as cabozantinib, vandetanib, lenvatinib and partially ponatinib, in different studies [ 58 , 80 , 95 ]. V804M/L mutations have also been reported in clinical experiences to confer resistance to vandetanib in RET-positive NSCLC patients [ 96 , 97 ].…”