| Autor: |
Kohale IN; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Yu J; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA., Zhuang Y; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA., Fan X; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA., Reddy RJ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Sinnwell J; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA., Kalari KR; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA., Boughey JC; Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA., Carter JM; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA., Goetz MP; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA.; Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA., Wang L; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA., White FM; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. |
| Abstrakt: |
Neoadjuvant chemotherapy (NAC) remains the cornerstone of the treatment for triple negative breast cancer (TNBC), with the goal of complete eradication of disease. However, for patients with residual disease after NAC, recurrence and mortality rates are high and the identification of novel therapeutic targets is urgently needed. We quantified tyrosine phosphorylation (pTyr)-mediated signaling networks in chemotherapy sensitive (CS) and resistant (CR) TNBC patient-derived xenografts (PDX), to gain novel therapeutic insights. The antitumor activity of SFK inhibition was examined in vivo. Treated tumors were further subjected to phosphoproteomic and RNAseq analysis, to identify the mechanism of actions of the drug. We identified Src Family Kinases (SFKs) as potential therapeutic targets in CR TNBC PDXs. Treatment with dasatinib, an FDA approved SFK inhibitor, led to inhibition of tumor growth in vivo. Further analysis of post-treatment PDXs revealed multiple mechanisms of actions of the drug, confirming the multi-target inhibition of dasatinib. Analysis of pTyr in tumor specimens suggested a low prevalence of SFK-driven tumors, which may provide insight into prior clinical trial results demonstrating a lack of dasatinib antitumor activity in unselected breast cancer patients. Taken together, these results underscore the importance of pTyr characterization of tumors, in identifying new targets, as well as stratifying patients based on their activated signaling networks for therapeutic options. Our data provide a strong rationale for studying SFK inhibitors in biomarker-selected SFK-driven TNBC. |
