Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways

Zhang, Siyuan; Huang, Wen Chien; Li, Ping; Guo, Hua; Poh, Say Bee; Brady, Samuel W.; Xiong, Yan; Tseng, Ling Ming; Li, Shau Hsuan; Ding, Zhaoxi; Şahin, Ayşegül; Esteva, Francisco J.; Hortobágyi, Gabriel N.; Yu, Dihua

doi:10.1038/nm.2309

Cited by 468 publications

(471 citation statements)

References 51 publications

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“…Therefore, inhibiting YB-1 function will likely increase sensitivity to trastuzumab by reducing the expression of MNK1, EGFR, DMSO BI-D1870 DMSO BI-D1870 DMSO BI-D1870 DMSO BI-D1870 DMSO BI-D1870 DMSO BI-D1870 BT474 HR6 HR5 SS SS EGF SS EGF EGF EV MNK1 % viable MET, CD44, the anti-apoptotic proteins mentioned above, and likely other mediators of resistance to the drug downstream from YB-1. For example, c-SRC was recently shown to promote trastuzumab resistance (Zhang et al, 2011). Our ChIP-sequencing analysis identified the non-receptor tyrosine kinase SRC-family member, YES, as a YB-1 target in the trastuzumabresistant HR5 and HR6 cells.…”

Section: Discussionmentioning

confidence: 80%

“…Heterodimerization of HER2 with EGFR or HER3 (Motoyama et al, 2002;Diermeier et al, 2005), hyperactivation of phosphatidylinositol-3-kinase (PI3K) signaling through loss of PTEN or PIK3CA mutations Berns et al, 2007;Junttila et al, 2009), overexpression or activation of MET (Shattuck et al, 2008), increases in insulin-like growth factor-1 receptor (IGF-1R) signaling from receptor overexpression or heterodimerization with HER2 (Lu et al, 2001;Camirand et al, 2002;Nahta et al, 2005), and activation of non-receptor tyrosine kinase c-SRC (Zhang et al, 2011) have all been implicated in decreased sensitivity to trastuzumab. In order to understand the mechanisms of trastuzumab resistance further, use of physiologically relevant models is essential.…”

Section: Introductionmentioning

confidence: 99%

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MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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Trastuzumab (Herceptin) resistance is a major obstacle in the treatment of patients with HER2-positive breast cancers. We recently reported that the transcription factor Y-box binding protein-1 (YB-1) leads to acquisition of resistance to trastuzumab in a phosphorylationdependent manner that relies on p90 ribosomal S6 kinase (RSK). To explore how this may occur we compared YB-1 target genes between trastuzumab-sensitive cells (BT474) and those with acquired resistance (HR5 and HR6) using genome-wide chromatin immunoprecipitation sequencing (ChIP-sequencing), which identified 1391 genes uniquely bound by YB-1 in the resistant cell lines. We then examined differences in protein expression and phosphorylation between these cell lines using the Kinexus Kinex antibody microarrays. Cross-referencing these two data sets identified the mitogen-activated protein kinase-interacting kinase (MNK) family as potentially being involved in acquired resistance downstream from YB-1. MNK1 and MNK2 were subsequently shown to be overexpressed in the resistant cell lines; however, only the former was a YB-1 target based on ChIP-PCR and small interfering RNA (siRNA) studies. Importantly, loss of MNK1 expression using siRNA enhanced sensitivity to trastuzumab. Further, MNK1 overexpression was sufficient to confer resistance to trastuzumab in cells that were previously sensitive. We then developed a de novo model of acquired resistance by exposing BT474 cells to trastuzumab for 60 days (BT474LT). Similar to the HR5/HR6 cells, the BT474LT cells had elevated MNK1 levels and were dependent on it for survival. In addition, we demonstrated that RSK phosphorylated MNK1, and that this phosphorylation was required for ability of MNK1 to mediate resistance to trastuzumab. Furthermore, inhibition of RSK with the small molecule BI-D1870 repressed the MNK1-mediated trastuzumab resistance. In conclusion, this unbiased integrated approach identified MNK1 as a player in mediating trastuzumab resistance as a consequence of YB-1 activation, and demonstrated RSK inhibition as a means to overcome recalcitrance to trastuzumab.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

et al. 2012

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“…According to a previous report, increased Src activation confers resistance to trastuzumab and targeting Src in combination with trastuzumab-sensitized trastuzumabresistant cell lines (23). In addition, the integrin/FAK/Src pathway is highly activated in lapatinib-resistant cells, and inhibition of these pathways overcomes lapatinib resistance (24).…”

Section: Saracatinib Enhances Antitumor Effects Of Lapatinib In Her2-mentioning

confidence: 98%

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

Nam

et al. 2013

Molecular Cancer Therapeutics

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Src is a nonreceptor tyrosine kinase involved in the cross-talk and mediation of many signaling pathways that promote cell proliferation, adhesion, invasion, migration, and tumorigenesis. Increased Src activity has been reported in many types of human cancer, including gastric cancer. Therefore, this factor has been identified as a promising therapeutic target for cancer treatments, and targeting Src in gastric cancer is predicted to have potent effects. We evaluated the antitumor effect of a c-Src/Abl kinase inhibitor, saracatinib (AZD0530), alone or combined with chemotherapeutic agents in gastric cancer cell lines and a NCI-N87 xenograft model. Among 10 gastric cancer cell lines, saracatinib specifically inhibited the growth and migration/invasion of SNU216 and NCI-N87 cells. Saracatinib blocked the Src/FAK, HER family, and oncogenic signaling pathways, and it induced G 1 arrest and apoptosis in SNU216 and NCI-N87 cells. Apoptosis required induction of the proapoptotic BCL2 family member Bim. Knockdown of Bim using siRNA decreased apoptosis induced by treatment with saracatinib, suggesting that Bim has an important role in saracatinibinduced apoptosis. Saracatinib enhanced the effects of lapatinib, an EGFR/HER2 dual inhibitor, in SNU216 and NCI-N87 cells. Furthermore, combined treatment with saracatinib and 5-fluorouracil (5-FU) or cisplatin exerted synergistic effects in both saracatinib-sensitive and saracatinib-resistant cells. Consistent with our in vitro findings, cotreatment with saracatinib and 5-FU resulted in enhanced antitumor activity in the NCI-N87 xenografts. These data indicate that the inhibition of Src kinase activity by saracatinib alone or in combination with other agents can be a strategy to target gastric cancer.

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“…Src regulates many fundamental cellular processes, including cell growth, differentiation, migration, and drug resistance (22,(29)(30)(31)(32). In our study, acquisition of acquired resistance to dovitinib is attributable to the activation of a Src-driven bypass signaling pathway.…”

Section: Discussionmentioning

confidence: 61%

“…These data suggest that integrin-mediated FAK activation may not be critically involved in acquired resistance to dovitinib in LC-2/ad DR cell. Instead, Src, as a common node downstream of multiple drug resistance pathways, might be activated by various signal inputs from specific RTKs, nonreceptor tyrosine kinases, or loss of protein tyrosine phosphatase activity (29,31). Therefore, it remains to be further studied what mediates the enhanced activity of Src.…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma

Kang

Jang

Sohn

et al. 2015

Molecular Cancer Therapeutics

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RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G 0 -G 1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src.

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Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways

Cited by 468 publications

References 51 publications

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

MKNK1 is a YB-1 target gene responsible for imparting trastuzumab resistance and can be blocked by RSK inhibition

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

Antitumor Activity and Acquired Resistance Mechanism of Dovitinib (TKI258) in RET-Rearranged Lung Adenocarcinoma

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