Reducing Skin Toxicities from EGFR Inhibitors with Topical BRAF Inhibitor Therapy.
Adult
Aged
Female
Humans
Male
Middle Aged
Acneiform Eruptions
/ chemically induced
Administration, Cutaneous
Antineoplastic Agents, Immunological
/ adverse effects
Cetuximab
/ adverse effects
Colorectal Neoplasms
/ drug therapy
Dermatologic Agents
/ administration & dosage
ErbB Receptors
/ antagonists & inhibitors
Panitumumab
/ adverse effects
Proto-Oncogene Proteins B-raf
/ antagonists & inhibitors
Treatment Outcome
Journal
Cancer discovery
ISSN: 2159-8290
Titre abrégé: Cancer Discov
Pays: United States
ID NLM: 101561693
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
22
12
2020
revised:
14
02
2021
accepted:
16
04
2021
pubmed:
30
4
2021
medline:
1
4
2022
entrez:
29
4
2021
Statut:
ppublish
Résumé
Treatment of cancer with EGFR inhibitors is limited by on-target skin toxicities induced by inhibition of the MAPK pathway. BRAF inhibitors are known to paradoxically activate the MAPK downstream of EGFR, which we confirmed using human skin keratinocytes. We then conducted a phase I clinical trial testing the hypothesis that topical therapy with the BRAF inhibitor LUT014 could improve skin toxicities induced by EGFR inhibitors. Ten patients with metastatic colorectal cancer who had developed acneiform rash while being treated with cetuximab or panitumumab were enrolled in three cohorts. LUT014 was well tolerated, and there were no dose-limiting toxicities. The acneiform rash improved in the 6 patients who started with grade 2 rash in the low and intermediate cohorts. We conclude that topical LUT014 is safe and efficacious in improving rash from EGFR inhibitors, consistent with the mechanism of action inducting paradoxical MAPK activation. SIGNIFICANCE: BRAF inhibitor topical therapy could avoid dose reductions of EGFR inhibitors, locally treating the main dose-limiting skin toxicity of this class of agents.
Identifiants
pubmed: 33910927
pii: 2159-8290.CD-20-1847
doi: 10.1158/2159-8290.CD-20-1847
pmc: PMC8418997
mid: NIHMS1697822
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
BRAF protein, human
EC 2.7.11.1
Cetuximab
PQX0D8J21J
Dermatologic Agents
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Panitumumab
6A901E312A
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
LUT014
0
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2158-2167Subventions
Organisme : NIAID NIH HHS
ID : U01 AI147462
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA197633
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : NIAMS NIH HHS
ID : U01 AR077511
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA244118
Pays : United States
Informations de copyright
©2021 The Authors; Published by the American Association for Cancer Research.
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