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Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.

ABSTRACT: Despite the development of new antineoplastic agents for the treatment of colorectal cancer (CRC), oxaliplatin and fluoropyrimidines remain the most commonly employed drugs for the treatment of both early and advanced disease. Intrinsic or acquired resistance is, however, an important limitation to pharmacological therapy, and the development of chemosensitization strategies constitute a major goal with important clinical implications. In the present work, we determined that high levels of activated Src kinase, measured as phospho-Src at the Tyr419 residue in CRC cell lines, can promote colorectal carcinoma cell resistance to oxaliplatin, but not to 5-fluorouracil (5FU), and that inhibition of this protein restores sensitivity to oxaliplatin. Similar results were observed with in vivo patient-derived xenograft (PDX) models that were orthotopically grown in murine livers. In PDX tumor lines derived from human CRC liver metastasis, dasatinib, a Src inhibitor, increases sensitivity to oxaliplatin only in tumors with high p-Src. However, dasatinib did not modify sensitivity to 5FU in any of the models. Our data suggest that chemoresistance induced by p-Src is specific to oxaliplatin, and that p-Src levels can be used to identify patients who may benefit from this combination therapy. These results are relevant for clinicians as they identify a novel biomarker of drug resistance that is suitable to pharmacological manipulation.

SUBMITTER: Perez M

PROVIDER: S-EPMC5078079 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.

Perez Marco M Lucena-Cacace Antonio A Marín-Gómez Luis Miguel LM Padillo-Ruiz Javier J Robles-Frias Maria Jose MJ Saez Carmen C Garcia-Carbonero Rocio R Carnero Amancio A

Oncotarget 20160501 22

Despite the development of new antineoplastic agents for the treatment of colorectal cancer (CRC), oxaliplatin and fluoropyrimidines remain the most commonly employed drugs for the treatment of both early and advanced disease. Intrinsic or acquired resistance is, however, an important limitation to pharmacological therapy, and the development of chemosensitization strategies constitute a major goal with important clinical implications. In the present work, we determined that high levels of activ ...[more]

PMID: 27105527

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Project description:The nonreceptor tyrosine kinase Src regulates multiple pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. It is robustly activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance in vitro and in vivo, but not after 5-fluorouracil (5-FU) alone. However, activation of Src and its substrate focal adhesion kinase (FAK) in metastatic colorectal cancer treated with oxaliplatin has not been investigated. We retrospectively evaluated the activation of Src and FAK in hepatic metastases of colorectal cancer and correlated these findings with the clinical outcomes of patients treated with oxaliplatin.Samples from 170 hepatic resections from patients with metastatic colorectal cancer from two cohorts were examined by IHC for expression of Src, activated Src (pSrc), FAK, and activated FAK (pFAK). Patients in the first cohort (120 patients) were analyzed for immunohistochemical protein expression and for survival outcomes. In the second cohort, tissue was collected from 25 patients undergoing sequential hepatic metastasectomies (n = 50).In the first cohort, Src activation was positively correlated with pFAK expression (P = 0.44, P < 0.001). Patients pretreated with oxaliplatin and 5-FU demonstrated increased expression of pFAK (P = 0.017) compared with patients treated with 5-FU alone or irinotecan/5-FU. Total Src expression was associated with the number of neoadjuvant cycles of oxaliplatin (P = 0.047). In the second cohort, pFAK expression was higher following exposure to oxaliplatin. When patients were stratified by expression of pFAK and pSrc, an inverse relationship was observed between relapse-free survival rates and levels of both pFAK (21.1 months, 16.5 months, and 7.4 months for low, medium, and high levels of pFAK, respectively; P = 0.026) and pSrc (19.6 months, 13.6 months, and 8.2 months, respectively; P = 0.013). No differences in overall survival were detected.Patients administered neoadjuvant oxaliplatin demonstrated higher levels of Src pathway signaling in hepatic metastases, a finding associated with poorer relapse-free survival. These results are consistent with prior in vitro studies and support the idea that combining Src inhibition with platinum chemotherapy warrants further investigation in metastatic colorectal cancer.

Project description:Purpose: Aberrant activation of the intracellular tyrosine kinase Src has been implicated as a mechanism of acquired chemotherapy resistance in metastatic colorectal cancer (mCRC). Here, the oral tyrosine kinase Src inhibitor, dasatinib, was investigated in combination with FOLFOX and cetuximab.Experimental Design: We performed a phase IB/II study of 77 patients with previously treated mCRC. Primary objectives were to determine the maximum tolerated dose, dose-limiting toxicities (DLT), pharmacodynamics, and efficacy. Using a 3 + 3 design, patients received FOLFOX6 with cetuximab and escalating doses of dasatinib (100, 150, 200 mg daily), followed by a 12-patient expansion cohort at 150 mg. Phase II studies evaluated FOLFOX plus dasatinib 100 mg in KRAS c12/13mut patients or in combination with cetuximab if KRAS c12/13WT FAK and paxillin were utilized as surrogate blood biomarkers of Src inhibition, and paired biopsies of liver metastases were obtained in patients in the expansion cohort.Results: In phase IB, the DLTs were grade 3/4 fatigue (20%) and neutropenia (23%). In phase II, grade 3/4 fatigue (23%) and pleural effusions (11%) were present. Response rates were 20% (6 of 30) in the phase IB escalation and expansion cohort and 13% (3 of 24) and 0% (0 of 23) in the KRAS c12/13WT and mutant cohorts of phase II, respectively. Median progression-free survival was 4.6, 2.3, and 2.3 months, respectively. There was no evidence of Src inhibition based on surrogate blood biomarkers or paired tumor biopsies.Conclusions: The combination of dasatinib plus FOLFOX with or without cetuximab showed only modest clinical activity in refractory colorectal cancer. This appears to be primarily due to a failure to fully inhibit Src at the achievable doses of dasatinib. The combination of dasatinib plus FOLFOX with or without cetuximab did not show meaningful clinical activity in refractory colorectal cancer due to failure to fully inhibit Src. Clin Cancer Res; 23(15); 4146-54. ©2017 AACR.

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Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.

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Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.

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