Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection

Huang, Fei; Reeves, Karen A.; Han, Xia; Fairchild, Craig; Platero, Suso; Wong, Tai W.; Lee, Francis; Shaw, Peter M.; Clark, Edwin

doi:10.1158/0008-5472.can-06-3633

Cited by 305 publications

(285 citation statements)

References 45 publications

Supporting

Mentioning

260

Contrasting

Order By: Relevance

“…Interestingly, dasatinib sensitively did not appear to correlate with the levels of Src activation in each cell line. Consistent with these findings, Src kinase failed to emerge as a marker predicting dasatinib sensitivity in breast cancer cell lines (41,42), underscoring the potential broad target specificity of this tyrosine kinase inhibitor (43,45). Although promising candidates have been identified, the direct mediators of dasatinib action in breast tumor cells remain to be confirmed.…”

Section: Discussionmentioning

confidence: 70%

“…We investigated the efficacy of the tyrosine kinase inhibitor dasatinib, currently in clinical use for the treatment of patients with refractory leukemias, as a single-agent in our preclinical assays. Although originally designed as a Src kinase family inhibitor, dasatinib appears to have broad tyrosine kinase specificity (43,45) and effectively inhibits breast tumor cell lines with the most aggressive phenotypes (41,42). Likewise, dasatinib suppressed each tumor cell line tested here including HER2Δ16-expressing trastuzumab-refractory tumor cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Dasatinib is currently in clinical trials for the treatment of solid tumors and has recently been shown to inhibit the growth and proliferation of multiple breast tumor cell lines (41,42). Although originally designed as a Src kinase family inhibitor, dasatinib displays broader than anticipated tyrosine kinase inhibitor activity including direct inhibition of receptor tyrosine kinases (42)(43)(44)(45).…”

Section: Her2δ16-expressing Cell Lines Are Sensitive To a Single-agenmentioning

confidence: 99%

See 2 more Smart Citations

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

Mitra

Brumlik

Okamgba

et al. 2009

Molecular Cancer Therapeutics

174

205

View full text Add to dashboard Cite

The HER2-targeted therapy trastuzumab is widely used for the treatment of patients with metastatic breast tumors overexpressing HER2. However, an objective response is observed in only 12% to 24% of patients treated with trastuzumab as a single agent and initial responders regress in <6 months (1-3). The reason for the clinical failure of trastuzumab in this setting remains unclear. Here we show that local lymph node-positive disease progression in 89% of breast cancer patients with HER2-positive tumors involves the HER2 oncogenic variant HER2Δ16. We further show that ectopic expression of HER2Δ16, but not wild-type HER2, promotes receptor dimerization, cell invasion, and trastuzumab resistance of NIH3T3 and MCF-7 tumor cell lines. The potentiated metastatic and oncogenic properties of HER2Δ16 were mediated through direct coupling of HER2Δ16 to Src kinase. Cotargeting of HER2Δ16 and Src kinase with the singleagent tyrosine kinase inhibitor dasatinib resulted in Src inactivation, destabilization of HER2Δ16, and suppressed tumorigenicity. Activated Src kinase was also observed in 44% of HER2Δ16-expressing breast carcinomas underscoring the potential clinical implications of coupled HER2Δ16 and Src signaling. Our results suggest that HER2Δ16 expression is an important genetic event driving trastuzumab-refractory breast cancer. We propose that successful targeted therapeutics for intervention of aggressive HER2-positive breast cancers will require a strategy to suppress HER2Δ16 oncogenic signaling. One possibility involves a therapeutic strategy employing single-agent tyrosine kinase inhibitors to disengage the functionally coupled oncogenic HER2Δ16 and Src tyrosine kinase pathways.

show abstract

Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Section: Her2δ16-expressing Cell Lines Are Sensitive To a Single-agenmentioning

confidence: 99%

See 1 more Smart Citation

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

Mitra

Brumlik

Okamgba

et al. 2009

Molecular Cancer Therapeutics

174

205

View full text Add to dashboard Cite

show abstract

“…In addition, a baseline pharmacodiagnostic sample would be simpler to obtain from a routine diagnostic biopsy, for example, as opposed to posttreatment (pharmacodynamic) signatures where a separate biopsy procedure would be required. When comparing the pancreas cancer susceptibility gene signature for bosutinib described here to that for breast cancer (18) and prostate cancer (19) with dasatinib, we did not find shared genes. There are several possibilities to explain this difference.…”

Section: Discussionmentioning

confidence: 59%

“…One important preclinical study found a six-gene predictor for dasatinib susceptibility of breast cancer cell lines, and this was associated with a "triple-negative" [estrogen receptor (ER), progesterone receptor (PR), HER2] pattern in archival human breast cancer specimens (18). Another used a panel of prostate cancer cell lines to identify a five-gene set predictor, several of which were down-regulated after dasatinib treatment (19).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

Messersmith

Rajeshkumar

Tan

et al. 2009

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Recently, Src tyrosine kinase has emerged as an attractive target for anticancer therapy, and Src is overexpressed in pancreatic cancer. The purpose of the study was to investigate the in vivo efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, using a panel of human pancreatic tumor xenografts. Surgically resected human pancreatic tumors were implanted into female nude mice and randomized to bosutinib versus control. Src and other pathways were analyzed by Western Blot, IHC, and Affymetrix U133 Plus 2.0 gene arrays. Of 15 patient tumors, 3 patient tumors were found to be sensitive to bosutinib, defined as tumor growth of <45% than that of control tumors. There were no definite differences between sensitive and resistant tumors in the baseline Src kinase pathway protein expression assessed by Western Blot. Caveolin-1 expression, as assessed by reverse transcription-PCR and immunohistochemistry, was frequently higher in sensitive cases. In sensitive tumors, bosutinib resulted in increased apoptosis. Phosphorylation of key signaling molecules downstream of Src, signal transducers and activators of transcription 3, and signal transducers and activators of transcription 3, were significantly inhibited by bosutinib. K-Top Scoring Pairs analysis of gene arrays gave a six-gene classifier that predicted resistance versus sensitivity in six validation cases. These results may aid the clinical development of bosutinib and other Src inhibitors in pancreas cancer.

show abstract

Dynamic expression of SNAI2 in prostate cancer predicts tumor progression and drug sensitivity

et al. 2022

View full text Add to dashboard Cite

Prostate cancer is a highly heterogeneous disease, understanding the crosstalk between complex genomic and epigenomic alterations will aid in developing targeted therapeutics. We demonstrate that, even though snail family transcriptional repressor 2 (SNAI2) is frequently amplified in prostate cancer, it is epigenetically silenced in this disease, with dynamic changes in SNAI2 levels showing distinct clinical relevance. Integrative clinical data from 18 prostate cancer cohorts and experimental evidence showed that gene fusion between transmembrane serine protease 2 (TMPRSS2) and ETS transcription factor ERG (ERG) (TMPRSS2–ERG fusion) is involved in the silencing of SNAI2. We created a silencer score to evaluate epigenetic repression of SNAI2, which can be reversed by treatment with DNA methyltransferase inhibitors and histone deacetylase inhibitors. Silencing of SNAI2 facilitated tumor cell proliferation and luminal differentiation. Furthermore, SNAI2 has a major influence on the tumor microenvironment by reactivating tumor stroma and creating an immunosuppressive microenvironment in prostate cancer. Importantly, SNAI2 expression levels in part determine sensitivity to the cancer drugs dasatinib and panobinostat. For the first time, we defined the distinct clinical relevance of SNAI2 expression at different disease stages. We elucidated how epigenetic silencing of SNAI2 controls the dynamic changes of SNAI2 expression that are essential for tumor initiation and progression and discovered that restoring SNAI2 expression by treatment with panobinostat enhances dasatinib sensitivity, indicating a new therapeutic strategy for prostate cancer.

show abstract

Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection

Cited by 305 publications

References 45 publications

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

Dynamic expression of SNAI2 in prostate cancer predicts tumor progression and drug sensitivity

Contact Info

Product

Resources

About