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Ras Pathway Activation and MEKi Resistance Scores Predict the Efficiency of MEKi and SRCi Combination to Induce Apoptosis in Colorectal Cancer.
Davis, Thomas Benjamin; Gupta, Shilpa; Yang, Mingli; Pflieger, Lance; Rajan, Malini; Wang, Heiman; Thota, Ramya; Yeatman, Timothy J; Pledger, Warren Jackson.
Afiliação
  • Davis TB; Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
  • Gupta S; Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
  • Yang M; Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
  • Pflieger L; Precision Genomics Translational Science Center, Intermountain Healthcare, Murray, UT 84107, USA.
  • Rajan M; Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
  • Wang H; Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
  • Thota R; Oncology Clinical Program, Intermountain Healthcare, Murray, UT 84107, USA.
  • Yeatman TJ; Department of Surgery, University of Utah, Salt Lake City, UT 84132, USA.
  • Pledger WJ; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Cancers (Basel) ; 14(6)2022 Mar 11.
Article em En | MEDLINE | ID: mdl-35326598
ABSTRACT
Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. The RAS pathway is activated in more than 55% of CRC and has been targeted for therapeutic intervention with MEK inhibitors. Unfortunately, many patients have de novo resistance, or can develop resistance to this new class of drugs. We have hypothesized that much of this resistance may pass through SRC as a common signal transduction node, and that inhibition of SRC may suppress MEK inhibition resistance mechanisms. CRC tumors of the Consensus Molecular Subtype (CMS) 4, enriched in stem cells, are difficult to successfully treat and have been suggested to evade traditional chemotherapy agents through resistance mechanisms. Here, we evaluate targeting two pathways simultaneously to produce an effective treatment by overcoming resistance. We show that combining Trametinib (MEKi) with Dasatinib (SRCi) provides enhanced cell death in 8 of the 16 tested CRC cell lines compared to treatment with either agent alone. To be able to select sensitive cells, we simultaneously evaluated a validated 18-gene RAS pathway activation signature score along with a 13-gene MEKi resistance signature score, which we hypothesize predict tumor sensitivity to this dual targeted therapy. We found the cell lines that were sensitive to the dual treatment were predominantly CMS4 and had both a high 18-gene and a high 13-gene score, suggesting these cell lines had potential for de novo MEKi sensitivity but were subject to the rapid development of MEKi resistance. The 13-gene score is highly correlated to a score for SRC activation, suggesting resistance is dependent on SRC. Our data show that gene expression signature scores for RAS pathway activation and for MEKi resistance may be useful in determining which CRC tumors will respond to the novel drug combination of MEKi and SRCi.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Cancers (Basel) Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies / Risk_factors_studies Idioma: En Revista: Cancers (Basel) Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos