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

Pérez, Manuel; Lucena-Cacace, Antonio; Marín-Gómez, L.M.; Padillo-Ruíz, Javier; Robles‐Frías, María José; Sáez, Carmen; Garcia-Carbonero, Rocío; Carnero, Amancio

doi:10.18632/oncotarget.8880

Cited by 29 publications

(26 citation statements)

References 49 publications

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“…It is downstream of EGFR, yet upstream of both the PI3K and MAPK pathways. Several drugs targeting SRC are available, including dasatinib (23,24) , and functional studies of CRC cell lines or patient-derived xenogratfs with 20q amplification are needed to assess whether the group of patients in this study may benefit from anti-SRC therapy.…”

Section: Discussionmentioning

confidence: 99%

Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival

Ptashkin

Pagan

Yaeger

et al. 2017

Molecular Cancer Research

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Here comprehensive analysis was performed on the molecular and clinical features of colorectal carcinoma (CRC) harboring chromosome 20q amplification. Tumor and normal DNA from patients with advanced CRC underwent next generation sequencing (NGS) via MSK-IMPACT and a subset of case samples were subjected to high resolution microarray (Oncoscan). Relationships between genomic copy number and transcript expression were assessed with The Cancer Genome Atlas (TCGA) CRC data. Of the CRC patients sequenced (n=401) with MSK-IMPACT, 148 (37%) had 20q gain, and 30 (7%) had 20q amplification. In both the MSK-IMPACT and TCGA datasets, BCL2L1 was the most frequently amplified 20q oncogene. However, SRC was the only recognized 20q oncogene with a significant inverse relationship between mRNA upregulation and RAS/RAF mutation (OR: -0.4 +/- 0.2, p=0.02). In comparison to 20q diploid CRC, 20q gain/amplification was associated with wild-type (WT) KRAS (p<0.001) and BRAF (p=0.01), microsatellite stability (MSS) (p<0.001), distal primary tumors (p<0.001), and mutant TP53 (p<0.001), but not stage. On multi-variate analysis, longer overall survival from date of metastasis was observed with chromosome 20q gain (p=0.02) or amplification (p=0.04) compared to diploid 20q.

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Section: Discussionmentioning

confidence: 99%

Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival

Ptashkin

Pagan

Yaeger

et al. 2017

Molecular Cancer Research

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“…Next, we harvested four fresh human colon cancer samples from patient direct derived tumors, PDXs, grown in mice (25). After tissue disaggregation, tumor samples were dissociated into single-cell suspension by enzymatic digestion.…”

Section: Nampt Induces Pluripotency Via Signaling Pathways That Contrmentioning

confidence: 99%

NAMPT Is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and Resistance to Therapy through Sirt1 and PARP

Lucena-Cacace

Otero-Albiol

Jiménez-García

et al. 2018

Clinical Cancer Research

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126

105

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Colorectal cancer is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide (NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance to tumors. Ectopic overexpression of nicotinamide phosphoribosil transferase () and shRNAs in colorectal cancer cell lines, tumorigenic and stemness properties and transcription measurement in culture and Transcriptional analysis in public databases. Therapeutic approaches. NAMPT, the rate-limiting enzyme responsible for the highest source of physiologic NAD biosynthesis, increases tumorigenic properties and induces cancer stem cell-like properties through pathways that control stem cell signaling, thus enriching the cancer-initiating cell (CIC) population. Furthermore, expression correlated with high levels of CIC-like cells in colon tumors directly extracted from patients, and transcription meta-analysis revealed that NAMPT is also a key factor that induces cancer stem pathways in colorectal cancer tumors. This effect is mediated by PARP and SIRT1. In addition, we report a novel-driven signature that stratifies prognosis from high to low expression groups. The NAMPT signature contained SIRT1 and PARP1 levels as well as other cancer stem cell-related genes. Finally, NAMPT inhibition increased the sensitivity to apoptosis in both NAMPT-expressing cells and tumorspheres. NAMPT represents a novel therapeutic target in colon cancer progression and relapse, particularly the CIC subset of human colon cancers. .

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“…An analysis by Perez et al could demonstrate the importance of SRC and its inhibitors stating that the inhibition of SRC sensitized liver metastatic colorectal carcinoma to oxaliplatin 49. Interestingly, in our study population, patients with a high pretreatment SRC expression seemed to have benefited from a treatment schedule including oxaliplatin.…”

Section: Discussionmentioning

confidence: 53%

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer

et al. 2017

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The cellular sarcoma gene (SRC) is a proto-oncogene encoding for a tyrosine kinase. SRC expression was determined in locally advanced rectal adenocarcinoma tissue from pretreatment biopsies and resection specimens. The expression level was correlated with clinicopathological parameters to evaluate the predictive and prognostic capacity.For this monocentric analysis 186 patients with locally advanced rectal cancer (median: 63.7 years; 130 men (69.9%), 56 women (30.1%)) were included. Patients with a carcinoma of the upper third of the rectum were treated with primary tumor resection (n=27; 14.5%). All other patients received a preoperative chemoradiotherapy (CRT) with 50.4 Gy and concomitant 5-fluorouracil (5-FU) or 5-FU+oxaliplatin followed by postoperative chemotherapy with 5-FU or 5-FU+oxaliplatin. SRC expression was determined with immunohistochemical staining from pretreatment biopsies (n=152) and residual tumor tissue from the resection specimens (n=163). The results were correlated with clinicopathological parameters and long-term follow-up.The expression of SRC was determined in pretherapeutic biopsies (mean H-Score: 229) and resection specimens (mean H-Score: 254). High SRC expression in pretherapeutic tumor samples significantly correlated with a negative postoperative nodal status (p=0.005). Furthermore an increased protein expression in residual tumor tissue was associated with fewer distant metastases (p=0.04). The overexpression of SRC in pretreatment tumor biopsies showed also a trend for a longer cancer-specific survival (CSS; p=0.05) and fewer local relapses (p=0.06) during long-term follow-up.High SRC expression in rectal cancer seems to be associated with a better long-term outcome. This finding could help in the future to stratify patients for a recurrence risk adapted postoperative treatment.

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

Cited by 29 publications

References 49 publications

Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival

Chromosome 20q Amplification Defines a Subtype of Microsatellite Stable, Left-Sided Colon Cancers with Wild-type RAS/RAF and Better Overall Survival

NAMPT Is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and Resistance to Therapy through Sirt1 and PARP

The Prognostic Value of Tyrosine Kinase SRC Expression in Locally Advanced Rectal Cancer

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