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

Solomon, Benjamin; Tan, Lavinia; Lin, Jessica J.; Wong, Stephen Q.; Hollizeck, Sebastian; Ebata, Kevin; Tuch, Brian B.; Yoda, Satoshi; Gainor, Justin F.; Sequist, Lecia V.; Oxnard, Geoffrey R.; Gautschi, Oliver; Drilon, Alexander; Subbiah, Vivek; Khoo, Christine; Zhu, Edward Y.; Nguyen, M.; Henry, Dahlia; Condroski, Kevin R.; Kolakowski, Gabrielle R.; Gómez, Eliana B.; Ballard, Joshua A.; Metcalf, Andrew T.; Blake, James F.; Dawson, Sarah-Jane; Blosser, Wayne; Stancato, Louis F.; Brandhuber, Barbara J.; Andrews, Steven D.; Robinson, Bruce G.; Rothenberg, S. Michael

doi:10.1016/j.jtho.2020.01.006

Cited by 220 publications

(173 citation statements)

References 26 publications

Supporting

Mentioning

168

Contrasting

Unclassified

Order By: Relevance

“…colleagues 17 reported RET G810 solvent front mutations as a mechanism of resistance to selpercatinib in five patients with RET fusion-positive NSCLC and RET-mutant medullary thyroid cancer, predicted to hinder drug binding based on structural modeling. However, the frequency of these RET mutations remained unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The relatively low prevalence and narrow spectrum of RET mutations may reflect the high anti-RET potency of selpercatinib and pralsetinib, although our findings will require validation in larger cohorts. Interestingly, despite the potency of pralsetinib and selpercatinib against the gatekeeper RET V804 mutations based on preclinical studies, 13,14 the study by Solomon et al 17 identified RET V804 and G810 mutations in trans in two selpercatinib-resistant cases and in cis in a minority of reads in one selpercatinib-resistant case. Further studies are needed to elucidate whether the gatekeeper mutations can confer resistance to selpercatinib and/or pralsetinib despite the preclinical evidence, and whether the spectra of RET resistance mutations (and non-RET resistance alterations) differ between selpercatinib and pralsetinib.…”

Section: Discussionmentioning

confidence: 99%

“…In the first patient with CCDC6-RET fusion, a RET G810S mutation was detected at progression on selpercatinib (case MGH7, previously published). 17 This patient had previously received multiple MKIs (e.g. ponatinib, alectinib, vandetanib) as well as pralsetinib, and had a post-pralsetinib/pre-selpercatinib biopsy (MGH1) which did not reveal any RET resistance mutations (Supplementary Table S2, available at https://doi.org/10.…”

Section: Ret Solvent Front Mutationsmentioning

confidence: 99%

“…As selpercatinib and pralsetinib are now standard therapies in advanced RET fusion-positive lung cancer and will be more widely used, it is paramount to understand the mechanisms of TKI resistance and inform the development of novel therapeutic strategies that can overcome resistance. In one recent study, Solomon and colleagues 17 reported RET G810R/S/C/V solvent front mutations that mediated acquired resistance to selpercatinib in three RET fusion-positive NSCLC and two RET-mutant medullary thyroid cancer cases. The frequency of RET-resistance mutations, however, remains undetermined.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

et al. 2020

View full text Add to dashboard Cite

Background: Rearranged during transfection (RET) gene fusions are a validated target in non-small-cell lung cancer (NSCLC). RET-selective inhibitors selpercatinib (LOXO-292) and pralsetinib (BLU-667) recently demonstrated favorable antitumor activity and safety profiles in advanced RET fusion-positive NSCLC, and both have received approval by the US Food and Drug Administration for this indication. Insights into mechanisms of resistance to selective RET inhibitors remain limited. Patients and methods: This study was performed at five institutions. Tissue and/or cell-free DNA was obtained from patients with RET fusion-positive NSCLC after treatment with selpercatinib or pralsetinib and assessed by nextgeneration sequencing (NGS) or MET FISH. Results: We analyzed a total of 23 post-treatment tissue and/or plasma biopsies from 18 RET fusion-positive patients who received an RET-selective inhibitor (selpercatinib, n ¼ 10; pralsetinib, n ¼ 7; pralsetinib followed by selpercatinib, n ¼ 1, with biopsy after each inhibitor). Three cases had paired tissue and plasma samples, of which one also had two serial resistant tissue specimens. The median progression-free survival on RET inhibitors was 6.3 months [95% confidence interval 3.6e10.8 months]. Acquired RET mutations were identified in two cases (10%), both affecting the RET G810 residue in the kinase solvent front. Three resistant cases (15%) harbored acquired MET amplification without concurrent RET resistance mutations, and one specimen had acquired KRAS amplification. No other canonical driver alterations were identified by NGS. Among 16 resistant tumor specimens, none had evidence of squamous or small-cell histologic transformation. Conclusions: RET solvent front mutations are a recurrent mechanism of RET inhibitor resistance, although they occurred at a relatively low frequency. The majority of resistance to selective RET inhibition may be driven by RET-independent resistance such as acquired MET or KRAS amplification. Next-generation RET inhibitors with potency against RET resistance mutations and combination strategies are needed to effectively overcome resistance in these patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ret Solvent Front Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

et al. 2020

View full text Add to dashboard Cite

show abstract

“…A recent study demonstrated that RET solvent-front mutations ( RET G810S/G810R/G810C) can cause on-target resistance to selective and multikinase RET inhibitors. 22 A better understanding of mechanisms of acquired resistance to selective RET inhibitors and frequency of resistant alterations would guide the development of novel agents and combination therapies directed towards further improvement of treatment outcomes for patients with RET-altered malignancies.…”

Section: Discussionmentioning

confidence: 99%

Systemic and CNS Activity of Selective RET Inhibition With Selpercatinib (LOXO-292) in a Patient With RET-Mutant Medullary Thyroid Cancer With Extensive CNS Metastases

Andreev-Drakhlin

Cabanillas

Amini

et al. 2020

JCO Precision Oncology

Self Cite

View full text Add to dashboard Cite

Neoplasms of the Thyroid

Ringel¹

2022

Holland‐Frei Cancer Medicine

View full text Add to dashboard Cite

Overview Thyroid cancer is the most common malignancy of a classical endocrine organ. The most common forms of thyroid cancer derive from follicular thyroid cells, are characterized by cellular and histological patterns (e.g., papillary and follicular thyroid cancer), and are associated with outstanding overall survivorship but a high frequency of disease persistence. Less commonly, thyroid cancers can derive from thyroid neuroendocrine C‐cells (medullary thyroid cancer) that can occur as part of defined genetic syndromes (e.g., multiple endocrine neoplasia type 2). Thyroid cancers can present as or develop into poorly differentiated or dedifferentiated (anaplastic thyroid cancer) that are associated with highly aggressive courses and poor outcomes. Over the past decade, a more individualized approach has been taken for patients with early‐stage thyroid cancer, with reduced emphasis on aggressive surgical approaches, expansion of active surveillance approaches, and reduced use and/or dosing strategies for radioiodine therapy (RAI) using I‐131. RAI, TSH suppression therapy, and for selected local recurrence, reoperation, and external beam radiation therapy remain cornerstones of therapy for patients with progressive or nonremitting forms of thyroid cancer. For those who do not respond to those treatments, or those with specific gene mutations, there has been expansion of options including the use of targeted inhibitors of mutated driver oncogenes in all forms of thyroid cancer, anti‐angiogenic multikinase inhibitors in patients with progressive differentiated thyroid cancers, and immune checkpoint inhibitors.

show abstract

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

Cited by 220 publications

References 26 publications

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

Mechanisms of resistance to selective RET tyrosine kinase inhibitors in RET fusion-positive non-small-cell lung cancer

Systemic and CNS Activity of Selective RET Inhibition With Selpercatinib (LOXO-292) in a Patient With RET-Mutant Medullary Thyroid Cancer With Extensive CNS Metastases

Neoplasms of the Thyroid

Contact Info

Product

Resources

About