2. Academic Validation
  3. EML4-ALK mediates resistance to KRAS G12C inhibition and induces an oncogenic dependency by rewiring signaling through the wild-type RAS pathway

EML4-ALK mediates resistance to KRAS G12C inhibition and induces an oncogenic dependency by rewiring signaling through the wild-type RAS pathway

  • Cancer Discov. 2026 Jun 22. doi: 10.1158/2159-8290.CD-25-0477.
Pietro Scaparone 1,  Alessia Mira 1,  Taek-Chin Cheong 2,  Enrico Patrucco 3,  Biagio Ricciuti 4,  Riccardo Gribaudo 1,  Edoardo Garbo 5,  Rossella Scardaci 1,  Ilenia Savinelli 1,  Sandra Vietti Michelina 3,  Igor Odintsov 6,  Elliott J Brea 7,  Roberto Mignacco 1,  Rafael B Blasco 8,  David Santamaría 9,  Claudia Voena 3,  Marco H Hofmann 10,  Ernest Nadal 11,  Silvia Novello 12,  Mark M Awad 13,  Roberto Chiarle 8,  Chiara Ambrogio 1
Affiliations

Affiliations

  • 1 University of Turin Turin, TO Italy.
  • 2 Boston Children's Hospital Boston, MA United States.
  • 3 University of Turin Torino Italy.
  • 4 Dana-Farber/Harvard Cancer Center Boston, Massachusetts United States.
  • 5 Dana-Farber Cancer Institute Boston, Massachusetts United States.
  • 6 University of California, San Francisco San Francisco, CA United States.
  • 7 Dana-Farber Cancer Institute Boston, MA United States.
  • 8 Boston Children's Hospital Boston United States.
  • 9 Consejo Superior de Investigaciones Científicas (CSIC) Salamanca Spain.
  • 10 Boehringer Ingelheim RCV GmbH & Co KG Vienna Austria.
  • 11 Institut Català d'Oncologia L'Hospitalet de Llobregat, Barcelona Spain.
  • 12 University of Turin Orbassano, TO Italy.
  • 13 Memorial Sloan Kettering Cancer Center Boston, Massachusetts United States.
PMID: 42329099 DOI: 10.1158/2159-8290.CD-25-0477
Abstract

KRAS mutations are common oncogenic drivers in human cancers, with the KRASG12C variant being a key target in lung adenocarcinoma (LUAD). Despite the FDA approval of KRASG12C-selective inhibitors, their clinical efficacy has been limited, as evidenced by trials showing modest response rates and resistance development through the selection of acquired genomic alterations. Our study explores the mechanisms underlying acquired EML4-ALK fusion in KRASG12C-driven tumors developing resistance to KRASG12C inhibitors and potential therapeutic strategies to overcome it. Our findings reveal that combined ALK/KRASG12C inhibition is an effective therapeutic approach in this context. Moreover, we observed that KRASG12C/EML4-ALK tumor cells kept under constant pressure with KRASG12C inhibitors exhibit sensitivity to single-agent ALK inhibitors, suggesting a potential for rationally designed sequential treatments. Mechanistically, EML4-ALK bypasses KRASG12C inhibition by activating wild-type Ras, highlighting an additional therapeutic opportunity for multi-selective Ras inhibitors under clinical investigation.

Figures
Products