A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

Ng, King Pan; Hillmer, Axel M.; Chuah, Charles; Juan, Wen Chun; Ko, Tun Kiat; Teo, Audrey S.M.; Ariyaratne, Pramila; Takahashi, Naoto; Sawada, Kenichi; Yao, Fei; Soh, Sheila; Lee, Wah Heng; Huang, John; Allen, John C.; Woo, Xing Yi; Nagarajan, Niranjan; Kumar, Vikrant; Thalamuthu, Anbupalam; Poh, Wan Ting; Ang, Ai Leen; Mya, Hae Tha; How, Gee Fung; Li, Yang; Koh, Liang Piu; Chowbay, Balram; Chang, Chia-Tien; Nadarajan, Veera Sekaran; Chng, Wee Joo; Than, Hein; Lim, Lay Cheng; Goh, Yeow Tee; Zhang, Shenli; Poh, Dianne; Tan, Patrick; Seet, Ju‐Ee; Ang, Mei‐Kim; Chau, Noan-Minh; Ng, Quan‐Sing; Tan, Daniel S.W.; Soda, Manabu; Isobe, Kazutoshi; Nöthen, Markus M.; Wong, Tien Yin; Shahab, Atif; Ruan, Xiaoan; Cacheux-Rataboul, Valère; Sung, Wing-Kin; Tan, Eng Huat; Yatabe, Yasushi; Mano, Hiroyuki; Soo, Ross A.; Chin, Tan Min; Lim, Wan-Teck; Ruan, Yijun; Ong, S. Tiong

doi:10.1038/nm.2713

Cited by 499 publications

(588 citation statements)

References 50 publications

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“…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

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et al. 2014

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

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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...

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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.

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“…158 Notably, a gene polymorphism that impairs the expression of BIM was found to explain the de novo resistance of BCR-ABL-driven CML to Gleevec and mutant EGFR-driven lung cancer to Iressa/ Tarceva in East Asian populations. 159 Anticancer drug-induced killing of tumour cells requires activation of BH3-only proteins by upstream signalling mediators, such as p53 or the glucocorticoid receptor. These upstream signal activators are frequently mutated, lost or silenced (e.g., due to epigenetic modifications) during tumour development or subsequently during emergence of therapyresistant cancer cells.…”

Section: The Role Of the Bcl-2-regulated Apoptotic Pathway In Cancer mentioning

confidence: 99%

The BCL-2 protein family, BH3-mimetics and cancer therapy

2015

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Escape from apoptosis is a key attribute of tumour cells and facilitates chemo-resistance. The 'BCL-2-regulated' or 'intrinsic' apoptotic pathway integrates stress and survival signalling to govern whether a cancer cell will live or die. Indeed, many pro-apoptotic members of the BCL-2 family have demonstrated tumour-suppression activity in mouse models of cancer and are lost or repressed in certain human cancers. Conversely, overexpression of pro-survival BCL-2 family members promotes tumorigenesis in humans and in mouse models. Many of the drugs currently used in the clinic mediate their therapeutic effects (at least in part) through the activation of the BCL-2-regulated apoptotic pathway. However, initiators of this apoptotic pathway, such as p53, are mutated, lost or silenced in many human cancers rendering them refractory to treatment. To counter such resistance mechanisms, a novel class of therapeutics, 'BH3-mimetics', has been developed. These drugs directly activate apoptosis by binding and inhibiting select antiapoptotic BCL-2 family members and thereby bypass the requirement for upstream initiators, such as p53. In this review, we discuss the role of the BCL-2 protein family in the development and treatment of cancer, with an emphasis on mechanistic studies using well-established mouse models of cancer, before describing the development and already recognised potential of the BH3-mimetic compounds.

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“…In particular, this pathway contributes to cellular demise during embryogenesis 1,2 and after DNA damage, loss of cytokine-or adhesion-induced signaling, or exposure to various chemotherapeutic agents. [3][4][5][6] Conversely, inhibition of the intrinsic pathway through elevated expression of antiapoptotic BCL2 family members 7,8 or loss of proapoptotic pathway components [8][9][10][11][12] contributes to neoplastic transformation. 13,14 Whether a specific cell will live or die reflects, in part, the balance between these pro-and antiapoptotic BCL2 family members.…”

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confidence: 99%

Measurement of BH3-only protein tolerance

et al. 2017

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The BCL2 family of proteins regulates cellular life and death decisions. Among BCL2 family members, BH3-only proteins have critical roles by neutralizing antiapoptotic family members, as well as directly activating BAX and BAK. Despite widespread occurrence of BH3-only protein upregulation in response to various stresses, this process is rarely quantified. Moreover, it is unclear whether all BH3-only proteins are equipotent at inducing cell death. Here we show that BH3-only proteins increase as much as 15-to 20-fold after various treatments and define a parameter, termed BH3-only tolerance, which measures how many copies of a particular BH3-only protein can be expressed before the majority of cells in a population undergo apoptosis. We not only assess the relative contributions of anti-and proapoptotic BCL2 family members to BH3-only tolerance, but also illustrate how the study of this parameter can be used to understand cellular sensitivity to anticancer drugs and new combinations. These observations provide a new quantitative framework for assessing apoptotic susceptibility under various conditions.

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A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

Cited by 499 publications

References 50 publications

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

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

The BCL-2 protein family, BH3-mimetics and cancer therapy

Measurement of BH3-only protein tolerance

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