Abstract 3151: Loss of Axin1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions

Picco, Gabriele; Petti, Consalvo; Centonze, Alessia; Torchiaro, Erica; Bardelli, Alberto; Medico, Enzo

doi:10.1158/1538-7445.am2017-3151

Cited by 18 publications

(21 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The growth of APC mutant organoids does not rely on Wnt or R-spondin1 5. Our organoid models offer a unique opportunity to study this process, since pre-existing cell models, including the two known RSPO fusion CRC cell lines, VACO6 and SNU-1411, do not require Wnt as part of their culture conditions 27 28. Therefore, we performed single-cell RNAseq analysis on the two RSPO fusion tumour-normal paired organoids (H011 and H019), with and without differentiation via Wnt withdrawal (online supplementary figure 1 and online supplementary table 3).…”

Section: Resultsmentioning

confidence: 99%

Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

Yan

Siu

et al. 2020

Gut

View full text Add to dashboard Cite

ObjectiveSporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs.DesignWe established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed.ResultsWe observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time.ConclusionsThese organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

show abstract

Section: Resultsmentioning

confidence: 99%

Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

Yan

Siu

et al. 2020

Gut

View full text Add to dashboard Cite

show abstract

“…Intrinsic resistance to the PORCN inhibitor has been observed in some pancreatic cancer cell lines harboring inactivating mutations of RNF43, although the resistance mechanism remains unclear [8]. 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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

“…However, these cells developed resistance to LGK974 within 3 months when cultured with a sublethal concentration of LGK974. Exome sequencing of the resistant VACO6 clone found truncating mutations in AXIN1 that are absent in the parental cell line (Picco et al, 2017). Interestingly, these truncating mutations have been reported in the Catalogue of Somatic Mutations in Cancer database as cancer-related somatic variants.…”

mentioning

confidence: 98%

Wnt Signaling and Drug Resistance in Cancer

2019

View full text Add to dashboard Cite

Wnts are secreted proteins that bind to cell surface receptors to activate downstream signaling cascades. Normal Wnt signaling plays key roles in embryonic development and adult tissue homeostasis. The secretion of Wnt ligands, the turnover of Wnt receptors, and the signaling transduction are tightly regulated and fine-tuned to keep the signaling output "just right." Hyperactivated Wnt signaling due to recurrent genetic alterations drives several human cancers. Elevated Wnt signaling also confers resistance to multiple conventional and targeted cancer therapies through diverse mechanisms including maintaining the cancer stem cell population, enhancing DNA damage repair, facilitating transcriptional plasticity, and promoting immune evasion. Different classes of Wnt signaling inhibitors targeting key nodes of the pathway have been developed and show efficacy in treating Wnt-driven cancers and subverting Wnt-mediated therapy resistance in preclinical studies. Several of these inhibitors have advanced to clinical trials, both singly and in combination with other existing US Food and Drug Administration-approved anti-cancer modalities. In the near future, pharmacological inhibition of Wnt signaling may be a real choice for patients with cancer. SIGNIFICANCE STATEMENTThe latest insights in Wnt signaling, ranging from basic biology to therapeutic implications in cancer, are reviewed. Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.

show abstract

Abstract 3151: Loss of Axin1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions

Cited by 18 publications

References 0 publications

Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

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

Wnt Signaling and Drug Resistance in Cancer

Contact Info

Product

Resources

About