Molecular ontology of drug tolerant persisters in HER2 positive breast cancer - Resubmission - 1

HER2 阳性乳腺癌耐药者的分子本体论 - 重新提交 - 1

基本信息

项目摘要

SUMMARY: “Targeted therapies” against “driver oncogenes” play key roles in the therapy of many tumors, including breast cancers caused by amplification of the gene encoding the receptor tyrosine kinase HER2 (HER2+ BC). In metastatic HER2+ BC, however, resistance occurs even to combinations of anti-cancer drugs, and preventing its emergence is essential for converting remissions to cures. “Drug-tolerant persisters” (DTPs) survive exposure to tyrosine kinase inhibitors (TKIs) and other anti-neoplastics in a non-proliferative, quiescent (dormant) state via reversible, non-genetic mechanisms. DTPs are implicated in resistance of EGFRmut non-small cell lung cancer (NSCLC), BRAFmut melanoma, and other cancers, but a potential role in in HER2+ BC had not been explored thoroughly. We found that HER2+ BC lines treated with HER2-TKIs (lapatinib, tucatinib) give rise to two types of DTPs, which have luminal or mesenchymal transcriptomes. As in other cell lines, a fraction of HER2+ BC cells transit stochastically through G0 after exiting mitosis, instead of proceeding directly into G1. Remarkably, luminal DTPs arose uniquely from these transient G0 cells (“pre- DTPs”), which also express a subset of DTP genes. HER2+ BCs are highly proliferative, yet like other tumors, they also have significant numbers of G0 (Ki67-) cells, and our initial analyses of samples from TKI-treated HER2+ BC patients comport with DTP generation from G0 cells. Thus, in contrast to current models, which contend that the drug-tolerant, quiescent state is induced by TKIs and other targeted therapies/chemotherapies, our data indicate that pre-DTPs might already be present in the drug-naïve population. We hypothesize that the chromatin of such transient, G0/pre-DTP cells has a globally distinct organization that primes them to induce the complete DTP transcriptome and become drug-tolerant upon TKI exposure. Whether this “G0 selection/induction” model applies to mesenchymal-like HER2+ DTPs, DTPs induced by other agents, and/or more broadly to bona fide HER2 tumors remains unclear. Because DTPs comprise a potential cellular reservoir for seeding stable resistance to HER2 TKIs and other targeted/conventional therapies, delineating their ontogenetic mechanisms could reveal novel cancer vulnerabilities and ultimately, new therapies. Our focus on the unique features of gene regulation in G0 cells could also have implications for tumor dormancy. This proposal joins experts in epigenetics/chromosome organization (SKOK) and cancer biology/cell signaling (NEEL) to address these timely, relevant questions Specifically, we will: (1) Characterize chromatin architecture and gene regulation in HER2-TKI pre-DTPs and DTPs from luminal-like HER2+ BC lines, (2) Test the hypothesis that HER2-TKI DTPs from mesenchymal HER2+ BC lines also arise from G0-like pre-DTPs and have condensin II-organized chromatin, and (3) Test the pathophysiological significance of lapatinib DTPs in in vivo models of HER2-TKI DTPs.
摘要:针对“驱动癌基因”的“靶向治疗”在许多肿瘤的治疗中发挥着关键作用。

项目成果

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BENJAMIN G. NEEL其他文献

BENJAMIN G. NEEL的其他文献

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{{ truncateString('BENJAMIN G. NEEL', 18)}}的其他基金

Molecular ontology of drug tolerant persisters in HER2 positive breast cancer - Resubmission - 1
HER2 阳性乳腺癌耐药者的分子本体论 - 重新提交 - 1
  • 批准号:
    10545025
  • 财政年份:
    2022
  • 资助金额:
    $ 70.23万
  • 项目类别:
Cancer Center Support Grant
癌症中心支持补助金
  • 批准号:
    10643036
  • 财政年份:
    2022
  • 资助金额:
    $ 70.23万
  • 项目类别:
Response and resistance to SHP2 inhibitors alone and in combination in Non-Small Cell Lung Cancer
非小细胞肺癌中单独使用和联合使用 SHP2 抑制剂的反应和耐药性
  • 批准号:
    10531929
  • 财政年份:
    2020
  • 资助金额:
    $ 70.23万
  • 项目类别:
Response and resistance to SHP2 inhibitors alone and in combination in Non-Small Cell Lung Cancer
非小细胞肺癌中单独使用和联合使用 SHP2 抑制剂的反应和耐药性
  • 批准号:
    10316237
  • 财政年份:
    2020
  • 资助金额:
    $ 70.23万
  • 项目类别:
Human Shp2 (Ptpn11) mutations and cardiac valve development
人类 Shp2 (Ptpn11) 突变与心脏瓣膜发育
  • 批准号:
    7319031
  • 财政年份:
    2007
  • 资助金额:
    $ 70.23万
  • 项目类别:
Human Shp2 (Ptpn11) mutations and cardiac valve development
人类 Shp2 (Ptpn11) 突变与心脏瓣膜发育
  • 批准号:
    7629640
  • 财政年份:
    2007
  • 资助金额:
    $ 70.23万
  • 项目类别:
Human Shp2 (Ptpn11) mutations and cardiac valve development
人类 Shp2 (Ptpn11) 突变与心脏瓣膜发育
  • 批准号:
    7614852
  • 财政年份:
    2007
  • 资助金额:
    $ 70.23万
  • 项目类别:
Human Shp2 (Ptpn11) mutations and cardiac valve development
人类 Shp2 (Ptpn11) 突变与心脏瓣膜发育
  • 批准号:
    7789554
  • 财政年份:
    2007
  • 资助金额:
    $ 70.23万
  • 项目类别:
EM LOCALIZATION OF PTP1B & RTK & PTP1B INTERACTIONS
PTP1B 的电子显微镜定位
  • 批准号:
    7358054
  • 财政年份:
    2006
  • 资助金额:
    $ 70.23万
  • 项目类别:
EM LOCALIZATION OF PTP1B & RTK & PTP1B INTERACTIONS
PTP1B 的电子显微镜定位
  • 批准号:
    7181350
  • 财政年份:
    2005
  • 资助金额:
    $ 70.23万
  • 项目类别:

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