Command Palette

Search for a command to run...

Preprint WatchMildOctober 14th, 2026

THERAPY RESISTANCE IN MELANOMA DRIVES CILIOGENESIS AND GLUTAMINE/ASPARTATE METABOLISM DEPENDENCY

Lugato, P.; Castro, R.; Thomas, C.; Pedretti, S.; Oberkersch, R.; Mitro, N.; Santoro, M. M.

Acquired resistance to targeted therapy in melanoma drives ciliogenesis and a dependency on glutamine and aspartate metabolism, proposing a metabolic vulnerability in the resistant state.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The preprint reports that therapy-resistant melanoma acquires a glutamine and aspartate metabolic dependency, which implies a combination strategy layered on BRAF pathway inhibition. Claidex holds one relevant failure, brimarafenib-mirdametinib-braf-melanoma-phase1-2-tolerability-termination, which stopped on tolerability rather than efficacy while combining a BRAF inhibitor with a MEK inhibitor. That record is a caution about combination burden rather than about the biology proposed here. Any metabolic agent added to BRAF pathway blockade will inherit an already constrained tolerability window, so the preprint's therapeutic implication should be scoped against overlapping toxicity before it is scoped against efficacy.

Abstract excerpt

Despite the remarkable success of new therapeutic approaches, a considerable number of melanoma patients still relapse on conventional therapies within two years and develop resistance. Alterations in metabolism, including amino acid availability and regulation of metabolic processes, have been implicated in acquired drug resistance. In this study, we developed in vitro and in vivo models of target therapy resistance (TTR) and identified a translational program that supports primary ciliogenesis in drug-resistant BRAF melanoma. We established that drug resistance enhances primary ciliogenesis, which is needed to respond and survive to combination therapy (CT). Mechanistically, impairing cilia formation (IFT88KO) rewires glutamine and aspartate metabolism. Overall, we provide a new molecular mechanism underlying therapy resistance that should be considered to tailored therapeutic strategies.

Matching Claidex post-mortems

1 of 1 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.