Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

Madan, Babita; McDonald, Mitchell; Foxa, Gabrielle E.; Diegel, Cassandra R.; Williams, Bart O.; Virshup, David M.

doi:10.1038/s41413-018-0017-8

Cited by 79 publications

(79 citation statements)

References 33 publications

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“…We speculate that one major evolutionary pressure on the function and expression of xenobiotic resistance mechanisms is the need to protect the microenvironment of the intestinal stroma from ingested toxins and microbial metabolites. Similar to the intestine, bone homeostasis is highly dependent on Wnt signaling, and PORCN inhibitors indeed affect bone regeneration (Madan et al, 2018). This suggests that evolutionary pressures imposed by local environmental factors drive the development of drug resistance limited to the intestinal stroma.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

et al. 2018

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The gut absorbs dietary nutrients and provides a barrier to xenobiotics and microbiome metabolites. To cope with toxin exposures, the intestinal epithelium is one of the most rapidly proliferating tissues in the body. The stem cell niche supplies essential signaling factors including Wnt proteins secreted by subepithelial myofibroblasts. Unexpectedly, therapeutically effective doses of orally administered PORCN inhibitors that block all Wnt secretion do not affect intestinal homeostasis. We find that intestinal myofibroblasts are intrinsically resistant to multiple xenobiotics, including PORCN inhibitors and the anthracycline antibiotic doxorubicin. These myofibroblasts have high expression of a subset of drug transporters; knockout of Mrp1/Abcc1 enhances drug sensitivity. Tamoxifen administration to Rosa26 mice visually highlights the drug-resistant intestinal stromal compartment and identifies small populations of drug-resistant cells in lung, kidney, and pancreatic islets. Xenobiotic resistance of the Wnt-producing myofibroblasts can protect the intestinal stem cell niche in the face of an unpredictable environment.

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Section: Discussionmentioning

confidence: 99%

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

et al. 2018

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“…It was also reported that long-term exposure to a PORCN inhibitor in vitro selected for a AXIN1-mutant clone in a RSPO3-translocated colorectal cancer cell line and the AXIN1 mutation drove acquired resistance to the PORCN inhibitor [20]. Moreover, on-target adverse effects of Wnt pathway blockade by PORCN inhibitors, including bone loss and dysgeusia, were observed in a preclinical study and clinical trials [21][22][23]. One strategy to overcome drug resistance and reduce adverse effects is synergistic drug combinations, through which lower drug doses can be used to achieve improved anticancer efficacy.…”

Section: Introductionmentioning

confidence: 95%

“…4a, b). As one goal of the study was to minimize the on-target side effects of PORCN inhibitor, we used a relatively low dose (5 mg/kg/day) of ETC-159 based on our prior studies [19,21]. In total, 5 mg/kg ETC-159 and 50 mg/kg GDC-0941 as single-agent treatment suppressed tumor growth by 68% and 51%, respectively, while the combination treatment suppressed tumor growth by 94%.…”

Section: Dual Wnt and Pi3k/mtor Pathway Inhibition Potently Blocks Inmentioning

confidence: 99%

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

et al. 2019

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Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is aggressive and lethal. Although there is an urgent need for effective therapeutics in treating pancreatic cancer, none of the targeted therapies tested in clinical trials to date significantly improve its outcome. PORCN inhibitors show efficacy in preclinical models of Wnt-addicted cancers, including RNF43mutant pancreatic cancers and have advanced to clinical trials. In this study, we aimed to develop drug combination strategies to further enhance the therapeutic efficacy of the PORCN inhibitor ETC-159. To identify additional druggable vulnerabilities in Wnt-driven pancreatic cancers, we performed an in vivo CRISPR loss-of-function screen. CTNNB1, KRAS, and MYC were reidentified as key oncogenic drivers. Notably, glucose metabolism pathway genes were important in vivo but less so in vitro. Knockout of multiple genes regulating PI3K/mTOR signaling impacted the growth of Wnt-driven pancreatic cancer cells in vivo. Importantly, multiple PI3K/mTOR pathway inhibitors in combination with ETC-159 synergistically suppressed the growth of multiple Wnt-addicted cancer cell lines in soft agar. Furthermore, the combination of the PORCN inhibitor ETC-159 and the pan-PI3K inhibitor GDC-0941 potently suppressed the in vivo growth of RNF43mutant pancreatic cancer xenografts. This was largely due to enhanced suppressive effects on both cell proliferation and glucose metabolism. These findings demonstrate that dual PORCN and PI3K/mTOR inhibition is a potential strategy for treating Wnt-driven pancreatic cancers.

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“…To date, WNT-targeted drugs have performed poorly in early phase clinical studies, owing to on-target dose-limiting toxicity, including bone fractures (51). Recent work has shown that combination of RANKL and PORCN inhibitors provide potent WNT pathway suppression while avoiding adverse bone-related effects (23). Based on this data, new combination trials have been launched, specifically targeting RSPO3 fusion CRC.…”

Section: Discussionmentioning

confidence: 99%

“…Long-term treatment with WNT974 can cause intestinal and bone damage in mice (22,23). To enable potent and sustained WNT suppression in tumor cells without effects on surrounding tissues, we used the regulatable shApc model, whereby withdrawal of dox from chow drives rapid APC restoration and potent WNT pathway suppression (10,11).…”

Section: The In Vivo Tumor Microenvironment Is Sufficient To Prime Cementioning

confidence: 99%

Lineage reversion drives WNT independence in intestinal cancer

Han

Goswami

et al. 2020

Preprint

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The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNTindependent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFb exposure drives YAP/ TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work delineates genetic and microenvironmental factors that drive WNT inhibitor resistance, identifies a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.

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Bone loss from Wnt inhibition mitigated by concurrent alendronate therapy

Cited by 79 publications

References 33 publications

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

Intrinsic Xenobiotic Resistance of the Intestinal Stem Cell Niche

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

Lineage reversion drives WNT independence in intestinal cancer

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