BIM Expression in Treatment-Naïve Cancers Predicts Responsiveness to Kinase Inhibitors

Faber, Anthony C.; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Chung, Euiheon; Incio, João; Digumarthy, Subba R.; Pollack, Sarah F.; Song, Youngchul; Muzikansky, Alona; Lifshits, Eugene; Roberge, Sylvie; Coffman, Erik J.; Benes, Cyril H.; Gómez, Henry Leonidas; Baselga, José; Arteaga, Carlos L.; Rivera, Miguel N.; Dias‐Santagata, Dora; Jain, Rakesh K.; Engelman, Jeffrey A.

doi:10.1158/2159-8290.cd-11-0106

Cited by 248 publications

(250 citation statements)

References 51 publications

(66 reference statements)

Supporting

Mentioning

234

Contrasting

Order By: Relevance

“…Recent studies suggest that this approach may be broadly effective in both IBC and non-IBC cells that have high basal levels of Bim-EL, as the effectiveness of targeting cancer cells with kinase inhibitors has been shown to strongly correlate with Bim-EL expression. 33 Our data provide a mechanistic rationale for these results and suggest that targeting ErbB2 or EGFR in IBC cells could be particularly effective given that the elevated Bim-EL expression could be rapidly targeted to the mitochondria upon kinase inhibition. Furthermore, recent studies have demonstrated that triplenegative breast cancer cells can be efficiently targeted by sequential treatment of an inhibitor of oncogenic signaling pathways followed by standard chemotherapy that causes DNA damage.…”

Section: Discussionmentioning

confidence: 63%

“…To expand on these findings, we extended these studies into MDA-MB-453 (453) and MDA-MB-361 (361) cells, which have previously been published to have high basal levels of Bim-EL protein. 33 However, the basal Bim-EL levels observed in the IBC cell lines are considerably elevated when compared with basal levels of Bim-EL in the 453 and 361 cells (Figure 4c). Additionally, in contrast to the IBC cell lines, ERK inhibition was sufficient to promote a significant increase in Bim-EL protein in the 453 and 361 cell lines ( Figure 4c).…”

Section: Resultsmentioning

confidence: 83%

See 1 more Smart Citation

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

View full text Add to dashboard Cite

Inflammatory breast cancer (IBC) is a rare and highly invasive type of breast cancer, and patients diagnosed with IBC often face a very poor prognosis. IBC is characterized by the lack of primary tumor formation and the rapid accumulation of cancerous epithelial cells in the dermal lymphatic vessels. Given that normal epithelial cells require attachment to the extracellular matrix (ECM) for survival, a comprehensive examination of the molecular mechanisms underlying IBC cell survival in the lymphatic vessels is of paramount importance to our understanding of IBC pathogenesis. Here we demonstrate that, in contrast to normal mammary epithelial cells, IBC cells evade ECM-detachment-induced apoptosis (anoikis). ErbB2 and EGFR knockdown in KPL-4 and SUM149 cells, respectively, causes decreased colony growth in soft agar and increased caspase activation following ECM detachment. ERK/MAPK signaling was found to operate downstream of ErbB2 and EGFR to protect cells from anoikis by facilitating the formation of a protein complex containing Bim-EL, LC8, and Beclin-1. This complex forms as a result of Bim-EL phosphorylation on serine 59, and thus Bim-EL cannot localize to the mitochondria and cause anoikis. These results reveal a novel mechanism that could be targeted with innovative therapeutics to induce anoikis in IBC cells.

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Resultsmentioning

confidence: 83%

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Apoptosis of tumor cells is sensitive to the changes in Bim protein levels, and various tyrosine kinase inhibitors (TKIs) are known to mediate apoptosis by up-regulation of Bim (34)(35)(36). Furthermore, low Bim levels have been associated with TKI resistance (37,38). Drugs mimicking the effects of the BH3-only proteins have been shown to induce apoptosis in different cancer models (39).…”

Section: Discussionmentioning

confidence: 99%

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β

Wiener

Band

Kallio

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

In the majority of microsatellite-stable colorectal cancers (CRCs), an initiating mutation occurs in the adenomatous polyposis coli (APC) or β-catenin gene, activating the β-catenin/TCF pathway. The progression of resulting adenomas is associated with oncogenic activation of KRas and inactivation of the p53 and TGF-β/Smad functions. Most established CRC cell lines contain mutations in the TGF-β/Smad pathway, but little is known about the function of TGF-β in the early phases of intestinal tumorigenesis. We used mouse and human ex vivo 3D intestinal organoid cultures and in vivo mouse models to study the effect of TGF-β on the Lgr5 + intestinal stem cells and their progeny in intestinal adenomas. We found that the TGF-β-induced apoptosis in Apc-mutant organoids, including the Lgr5 + stem cells, was mediated by up-regulation of the BH3-only proapoptotic protein Bcl-2-like protein 11 (Bim). BH3-mimetic compounds recapitulated the effect of Bim not only in the adenomas but also in human CRC organoids that had lost responsiveness to TGF-β-induced apoptosis. However, wild-type intestinal crypts were markedly less sensitive to TGF-β than Apcmutant adenomas, whereas the KRas oncogene increased resistance to TGF-β via the activation of the Erk1/2 kinase pathway, leading to Bim down-regulation. Our studies identify Bim as a critical mediator of TGF-β-induced apoptosis in intestinal adenomas and show that the common progression mutations modify Bim levels and sensitivity to TGF-β during intestinal adenoma development.A ctivation of the β-catenin/TCF transcription factor (Wnt) pathway is the initiating event in the majority of human colorectal cancers (CRCs) and one of the key regulators of CRC pathogenesis (1, 2). The β-catenin level in cells is controlled through a multiprotein complex that contains the adenomatous polyposis coli (APC) protein. In 70-80% of individuals suffering from the sporadic version of CRC, both APC alleles are mutated and thus inactivated, resulting in elevated nuclear β-catenin levels (1). Recently, the intestinal stem cells have been identified as the cells of origin of CRC (3, 4).According to the model presented by Fearon and Vogelstein (5), the initiating APC or CTNNB1 mutation is followed by oncogenic activation of the KRAS gene and inactivation of the TGF-β signal transduction pathway and the TP53 tumor suppressor. Recent genome-wide analysis by the Cancer Genome Atlas Network has demonstrated the high frequency of mutations in the β-catenin/TCF, TGF-β, phosphoinositide 3-kinase (PI3K) and p53 pathways in CRC (6). Full understanding of the roles of the driver mutations in colorectal tumors has been hampered by lack of appropriate ex vivo model systems for studies of CRC progression, and thus it has been difficult to study the effects of TGF-β in intestinal adenoma cells at the early stages of tumor development. Although TGF-β receptors have been deleted in Apc-mutant mouse models of CRC (7,8), these studies do not reveal the mechanism of TGF-β action in intestinal adenomas or give further i...

show abstract

“…Several preclinical studies have pointed out that BIM induction by inhibition of the MEK-ERK pathway plays a key role in apoptosis of oncogene-addicted solid cancer cells including EGFR -mutant NSCLC ( 4 , 5 ), HER2-amplified breast cancer ( 5 , 6 ), and BRAF -mutant colorectal cancer or melanoma cells ( 7 ). In this issue of Cancer Discovery , Faber and colleagues ( 8 ) demonstrate that knockdown of BIM expression protects HER2 -amplified and PIK3CA -mutant breast cancer cells against apoptosis induced by the EGFR/HER2 TKI lapatinib and the PI3K/mTOR inhibitor NVP-BEZ235, respectively. These results not only confirm previous results ( 4 , 6 , 7 ), but also suggest that BIM expression is critical for apoptosis even in PIK3CA-mutant cells treated with NVP-BEZ235, which does not affect the MEK-ERK pathway.…”

Section: In the Spotlightmentioning

confidence: 99%

The Potential Benefits of BIM in the Further Pursuit of Biomarker Discovery in Cancer Therapeutics

Yoshida

Haura

2011

Cancer Discovery

View full text Add to dashboard Cite

Summary:In this issue of Cancer Discovery, Faber and colleagues demonstrate that the basal expression of BIM is positively correlated with the amount of apoptosis induced by the corresponding tyrosine kinase inhibitor treatment within the same subtype of several oncogene-addicted cancer cell types. Their results suggest that pretreatment assessment of BIM levels can identify patients who would benefit from molecularly targeted therapies even after biomarker-based patient selection. Cancer Discovery; 1(4); 289-90.

show abstract

BIM Expression in Treatment-Naïve Cancers Predicts Responsiveness to Kinase Inhibitors

Cited by 248 publications

References 51 publications

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Anoikis evasion in inflammatory breast cancer cells is mediated by Bim-EL sequestration

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β

The Potential Benefits of BIM in the Further Pursuit of Biomarker Discovery in Cancer Therapeutics

Contact Info

Product

Resources

About