2. Academic Validation
  3. SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition

SRC kinase drives multidrug resistance induced by KRAS-G12C inhibition

  • Sci Adv. 2024 Dec 13;10(50):eadq4274. doi: 10.1126/sciadv.adq4274.
Xinxin Song 1,  Zhuan Zhou 1,  Ammar Elmezayen 2,  Runliu Wu 1,  Chunhua Yu 1,  Boning Gao 3,  John D Minna 3,  Kenneth D Westover 2,  Herbert J Zeh 1,  Guido Kroemer 4 5 6,  Lynn E Heasley 7 8,  Rui Kang 1,  Daolin Tang 1
Affiliations

Affiliations

  • 1 Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2 Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3 Hamon Center for Therapeutic Oncology Research, Department of Pharmacology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4 Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France.
  • 5 Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France.
  • 6 Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  • 7 Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 8 Eastern Colorado VA Healthcare System, Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA.
PMID: 39661665 DOI: 10.1126/sciadv.adq4274
Abstract

Direct targeting of the KRAS-G12C-mutant protein using covalent inhibitors (G12Ci) acts on human non-small cell lung Cancer (NSCLC). However, drug resistance is an emerging concern in this approach. Here, we show that MRTX849, a covalent inhibitor targeting the KRAS-G12C mutation, leads to the reactivation of the mitogen-activated protein kinase signaling pathway in MRTX849-resistant NSCLC and pancreatic ductal adenocarcinoma. A genome-wide CRISPR screen revealed that the adenosine triphosphate binding cassette transporter ABCC1 mediates MRTX849 resistance. Functional studies demonstrated that the transcription factor JUN drives ABCC1 expression, resulting in multidrug resistance. An unbiased drug screen identified the tyrosine kinase inhibitor dasatinib that potentiates MRTX849 efficacy by inhibiting SRC-dependent JUN activation, avoiding multidrug resistance and tumor suppression in vitro as well as in suitable preclinical mouse models and patient-derived organoids. Src inhibitors (DGY-06-116, dasatinib, and bosutinib) also exhibit synergistic effects with MRTX849 in eliminating various tumor cell lines carrying KRAS-G12C mutations. Thus, Src inhibitors amplify the therapeutic utility of G12Ci.

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