The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index; 31 of the 37 sources its claims cite were checked for support.
Ovarian Cancers with Low CIP2A Tumor Expression Constitute an APR-246–Sensitive Disease Subtype
Open accessPublished version of a preprint
Abstract
Identification of ovarian cancer patient subpopulations with increased sensitivity to targeted therapies could offer significant clinical benefit. We report that 22% of the high-grade ovarian cancer tumors at diagnosis express CIP2A oncoprotein at low levels. Furthermore, regardless of their significantly lower likelihood of disease relapse after standard chemotherapy, a portion of relapsed tumors retain their CIP2A-deficient phenotype. Through a screen for therapeutics that would preferentially kill CIP2A-deficient ovarian cancer cells, we identified reactive oxygen species inducer APR-246, tested previously in ovarian cancer clinical trials. Consistent with CIP2A-deficient ovarian cancer subtype in humans, CIP2A is dispensable for development of MISIIR-Tag–driven mouse ovarian cancer tumors. Nevertheless, CIP2A-null ovarian cancer tumor cells from MISIIR-Tag mice displayed APR-246 hypersensitivity both in vitro and in vivo. Mechanistically, the lack of CIP2A expression hypersensitizes the ovarian cancer cells to APR-246 by inhibition of NF-κB activity. Accordingly, combination of APR-246 and NF-κB inhibitor compounds strongly synergized in killing of CIP2A-positive ovarian cancer cells. Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient ovarian cancer tumor subtype patients. Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.
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Claims the paper makes
31 of 37 cited sources checked · 16 supported · 0 flagged · accuracy not yet measured
- Interpretationcitation
CIP2A associates with more aggressive ovarian cancer disease.
“It is dispensable for both human and mouse OvCa tumorigenesis, but associates with more aggressive disease (8)(Supplementary Table S1), and drives resistance to APR-246 therapy.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Bockelman, 2011, Prognostic role of CIP2A expression in serous ovarian cancer, Br J Cancer source
- Findingown data
APR-246 plus NF-kB inhibition was also effective in patient-derived ovarian cancer cell line OC002.
“Finally, the combined action of APR-246 and NF-kB inhibition was validated in patient-derived OvCa cell line OC002 derived from a patient with disseminated disease (Fig. 4I)(11).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] Kaipio, 2020, ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors, J Pathol source
The drug-sensitivity testing section reports results for patient-derived lines M019i, M068i, and M022i, but does not report an APR-246/NF-κB inhibitor combination in OC002. Searches for APR-246, OC002, and NF-κB inhibition found no passage describing the claimed validation; the NF-κB mention is in a reference to a different study (References; page unavailable). (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Interpretationreasoning
The APR-246 hypersensitivity of CIP2A-silenced ovarian cancer cells is unlikely to be mediated solely by mutant TP53 reactivation because the sensitive cell lines have varying TP53 status.
“Therefore, it is unlikely that the cell killing effects by APR-246 in the tested OvCa cells would be mediated solely by its mutant TP53 reactivating activity.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [25] Yoshikawa, 2016, PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells, Oncol Rep source
The Discussion reports that PRIMA-1MET killed ovarian cancer cell lines regardless of TP53 status, and the ROS-scavenger results support a mechanism beyond mutant-p53 reactivation. However, the source does not study CIP2A-silenced cells or establish that their APR-246 hypersensitivity has the same mechanism. (LLM, conf=0.84)
Experimental — accuracy not yet measured
- Findingcitation
MISIIR-TAg mice with wild-type and homozygous CIP2A deficiency show similar ovarian tumor development.
“we reported recently that there is no difference in OvCa tumorigenesis between MISIIR-TAg X CIP2AWT and MISIIR-TAg X CIP2AHOZ mice (17)(Fig. 2E).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [17] Laine, 2021, CIP2A interacts with TopBP1 and drives basal-like breast cancer tumorigenesis, Cancer Res source
- Findingown data
Even with a non-dephosphorylatable MEKK3S250D/T516D mutant, CIP2A inhibition reduces NF-kB activity.
“However, CIP2A inhibition was able to blunt NF-kB activity also in cells overexpressing MEK mutant with non-dephoshorylatable serine 250 and threonine 516 (MEKK3S250D/T516D) (34)(Fig. 4E; lane 7 vs. 8).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [34] Sun, 2010, Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IkappaB kinase beta/nuclear factor-kappaB activation, J Biol Chem source
The Results (Fig. 1E) test PP2Ac overexpression with a MEKK3 T516E/S520D mutant, not CIP2A inhibition with the stated S250D/T516D mutant. Our copy contains no passage addressing whether CIP2A inhibition reduces NF-κB activity in those cells; the citing sentence assigns that observation to its own Fig. 4E. (LLM, conf=0.78)
Experimental — accuracy not yet measured
- Interpretationown data
Knowing CIP2A status in recurrent ovarian tumors may help predict clinical response to APR-246.
“These results indicate that diagnostic identification of CIP2A status in recurrent OvCa tumors could have predictive potential for these patients regarding clinical responsiveness to APR-246 currently in clinical development (22,23).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [22] Cluzeau, 2021, Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase ii study by the groupe francophone des myelodysplasies (GFM), J Clin Oncol source
- cites [23] Basu, 2016, PISARRO: A EUTROC phase 1b study of APR-246 with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in relapsed platinum-sensitive high grade serous ovarian cancer (HGSOC), Ann Oncol source
- Rests on an assumption: The limited number of relapsed ascites samples (n=10) is representative of relapsed high-grade serous ovarian cancer.
- Interpretationcitation
In CIP2A-deficient cells, increased PP2A activity dephosphorylates RelA and shuts down downstream NF-kB signaling.
“This can be owed to higher PP2A activity in CIP2A deficient cells leading to dephosphorylation of RelA and inactivation of the NF-kB downstream signalling (35,36).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [35] Yang, 2001, Protein phosphatase 2A interacts with and directly dephosphorylates RelA, J Biol Chem source
The Results and Discussion passages show that PP2A directly dephosphorylates RelA, and the paper links deficient PP2A activity in melanoma cells to higher RelA phosphorylation and NF-κB activity. It does not study CIP2A-deficient cells or show that CIP2A deficiency raises PP2A activity and shuts down downstream NF-κB signaling. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [36] Hsieh, 2014, PMC, a potent hydrophilic α-tocopherol derivative, inhibits NF-κB activation via PP 2A but not IκBα-dependent signals in vascular smooth muscle cells, J Cell Mol Med source
The Results and Discussion (page not available) link PP2A to reduced p65/RelA phosphorylation and NF-κB activity in PMC-treated, LPS/IFN-γ-stimulated vascular smooth muscle cells. They do not examine CIP2A-deficient cells or establish that CIP2A deficiency increases PP2A activity, so the claim extends the reported mechanism to an unstudied condition. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Interpretationcitation
CIP2A supports NF-kB activity in ovarian cancer cells.
“On the other hand, the identified role of CIP2A in supporting NF-kB activity in OvCa cells is consistent with recent results from breast cancer cells (27).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [27] Guo, 2020, Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression, EMBO J source
- Premisecitation
Prior work reports high CIP2A expression in 68-83% of high-grade serous ovarian tumors.
“High CIP2A expression has been observed in 68-83% of high-grade serous OvCa tumors, and this associates with high proliferation index, aneuploidy, advanced tumor grade, TP53 mutation, and EGFR expression (8,9).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [8] Bockelman, 2011, Prognostic role of CIP2A expression in serous ovarian cancer, Br J Cancer source
The Results (Immunohistochemistry; Association to clinicopathological variables and biomarkers, page not provided) report that cytoplasmic CIP2A positivity was more frequent in high-grade serous ovarian cancers. They do not report high CIP2A expression in 68–83% of high-grade tumors: strong expression was found in 40.4% of all scored serous specimens, while weak and strong positivity together accounted for 82.8%. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [9] Fang, 2012, CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis, Tumor Biology source
- Premisecitation
In cultured ovarian cancer cells, CIP2A protects against apoptosis caused by cisplatin.
“CIP2A was recently also shown in cell culture to protect OvCa cells from Cisplatin-induced apoptosis (10), and to associate with stemness features in patient-derived high grade serous cancer (HGSC) cells (11).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [10] Li, 2019, Cancerous inhibitor of protein phosphatase 2A regulates cisplatin resistance in ovarian cancer, Oncol Lett source
- Premisecitation
Two drug-response screens found that reducing CIP2A made HeLa and KRAS-mutant lung cancer cells more responsive to several therapies.
“Further, in two cancer drug response screens, CIP2A depletion was shown to increase the therapeutic response of HeLa and KRAS-mutant lung cancer cells to various cancer therapies (12,13).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [12] Kauko, 2020, Phosphoproteome and drug-response effects mediated by the three protein phosphatase 2A inhibitor proteins CIP2A, SET, and PME-1, J Biol Chem source
The drug-response results (Fig. 6; page unavailable) report a screen of 238 cancer drugs in HeLa cells and say CIP2A depletion affected sensitivity to some drugs. The paper mentions an A549 lung-cancer phosphoproteome from a previous study, but our copy does not report a second drug-response screen showing that CIP2A depletion sensitized KRAS-mutant lung-cancer cells. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [13] Kauko, 2018, PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells, Sci Transl Med source
- Interpretationcitation
These results reinforce prior suggestions that CIP2A-deficient tumors may be more responsive to therapy.
“The results also support the earlier findings that CIP2A-deficient tumors could constitute a more therapy sensitive subtype (10,12,13).”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [10] Li, 2019, Cancerous inhibitor of protein phosphatase 2A regulates cisplatin resistance in ovarian cancer, Oncol Lett source
The Discussion reports that CIP2A depletion increased ovarian cancer cell sensitivity to cisplatin, supporting the suggested link between low CIP2A and treatment sensitivity. The study tested ovarian cancer cell lines, however, not whether CIP2A-deficient tumors constitute a therapy-sensitive subtype or respond better to therapies generally. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [12] Kauko, 2020, Phosphoproteome and drug-response effects mediated by the three protein phosphatase 2A inhibitor proteins CIP2A, SET, and PME-1, J Biol Chem source
In the Systemic analysis section (page unavailable), CIP2A depletion had drug-sensitivity effects similar to SET depletion, though smaller, and the authors suggest that PAIP expression might help stratify patients for therapy. The reported drug-response experiments were in cancer cells, however; the paper does not establish that CIP2A-deficient tumors are a more therapy-sensitive subtype. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [13] Kauko, 2018, PP2A inhibition is a druggable MEK inhibitor resistance mechanism in KRAS-mutant lung cancer cells, Sci Transl Med source
- Findingown data
NAC pre-treatment completely prevents APR-246-induced death of MISIIR-TAg X CIP2AHOZ cells.
“Also, similar to human cells, APR-246-elicited cell killing of MISIIR-TAg X CIP2AHOZ cells was fully rescued by NAC pre-treatment (Fig. 2H).”
Quote in the paperSubstantial claim - Findingown data
APR-246 caused a significantly different average percentage change in tumor volume between the two CIP2A genotypes.
“The average percentual change in tumor volume was significantly different between the genotypes (Fig. 2K).”
Quote in the paperSubstantial claim - Findingown data
CIP2A silencing increases APR-246 sensitivity across multiple ovarian cancer cell lines, including TYK-NU, TYK-NU.CPR, HEY, CAOV-3, NIH:OVCAR3, SKOV-3, and OVCAR-8.
“TYK-NU-CIP2AshRNA cells showed dramatically decreased EC50 values for APR-246 as compared to control shRNA expressing cells, and there was no difference between CIP2A silenced cells expressing two independent CIP2A shRNA sequences (Fig. 1C).”
- Also stated in: § Screening for therapeutics that preferentially kill CIP2A-deficient OvCa cells · plain
“In all cell lines transient CIP2A silencing resulted in increased sensitivity to APR-246 in a cell viability assay (Supplementary Fig. S1D).”
Quote in the paperSubstantial claim - Also stated in: § Screening for therapeutics that preferentially kill CIP2A-deficient OvCa cells · plain
- Findingown data
CIP2A negativity at diagnosis predicts a lower likelihood of disease relapse after chemotherapy.
“CIP2A negativity also very significantly predicted lower likelihood for disease relapse after chemotherapy (Supplementary Table S1).”
Quote in the paperNot a substantial claim - Findingown data
Nuclear p65 is significantly more abundant in HEY control cells than in HEY-CIP2AshRNA cells, with or without TNF-α treatment.
“HEY-CTLshRNA cells had a significantly higher proportion of nuclear p65 than HEY-CIP2AshRNA cells in both control and TNF-α treated cells (Fig. 4B and Supplementary Fig. S4C).”
Quote in the paperSubstantial claim - Findingown data
Among serous ovarian cancer patients who achieved complete response after standard chemotherapy, CIP2A-negative tumors were more frequent in those achieving complete response than CIP2A-positive tumors (57% vs 45%, p=0.044).
“Notably, patients with CIP2A negative OvCa tumor at diagnosis significantly more often achieved complete response (CR) than patients with CIP2A positive tumor (57% vs. 45%, chi squared test p-value 0.044).”
Quote in the paperNot a substantial claim - Findingown data
Combining PS-1145 with APR-246 produces a synthetic lethal effect in HEY control cells resembling that of APR-246 alone in HEY-CIP2AshRNA cells.
“With the chosen dose, NF-kB inhibitor PS-1145 did not have any notable effect on either HEY-CTLshRNA or HEY-CIP2AshRNA cells, but in combination with APR-246 it induced a similar synthetic lethal phenotype that was observed with APR-246 in HEY-CIP2AshRNA cells (Fig. 4H).”
Quote in the paperSubstantial claim - Findingown data
RNA sequencing found 147 genes with lower expression and 249 with higher expression in HEY control cells versus HEY-CIP2AshRNA cells.
“We identified 147 genes that were underexpressed, and 249 genes that were overexpressed, in HEY-CTLshRNA as compared to HEY-CIP2AshRNA cells (Fig. 3A, Log2 FC >1, p≤0.05; Supplementary Table S2).”
Quote in the paperNot a substantial claim - Findingown data
A portion of relapsed high-grade serous ovarian cancer ascites samples have low CIP2A expression (4 of 10).
“a portion of relapsed tumors retain their CIP2A-deficient phenotype.”
- Also stated in: § Low CIP2A expression confers OvCa cell APR-246 hypersensitivity in vivo · boosted
“Importantly, 4/10 of the relapsed HGSC samples (#5, #6, #8, and #10) could be clearly defined to have low CIP2A expression as compared to the rest of the tumors (Supplementary Fig. S3E).”
Quote in the paperSubstantial claim - Also stated in: § Low CIP2A expression confers OvCa cell APR-246 hypersensitivity in vivo · boosted
- Findingown data
p65 phosphorylation is lower in TNF-treated HEY-CIP2AshRNA cells.
“These changes correlated with lower p65 phosphorylation in TNF-treated HEY-CIP2AshRNA cells (Fig. 4C,D).”
Quote in the paperSubstantial claim - Findingown data
Gene set enrichment analysis linked three programs-EMT, TNFA signaling through NF-kB, and MYC targets-to the expression differences between HEY control and CIP2A-silenced cells.
“In the GSEA analysis, three transcriptional programs; Epithelial Mesenchymal Transition (EMT), TNFA signaling via NF-kB (NF-kB), and MYC targets, were significantly associated with differential gene expression profiles between HEY-CTLshRNA and HEY-CIP2AshRNA cells (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data
Each of three NF-kB inhibitors enhanced APR-246's ability to reduce viability in HEY control cells.
“As a result, all three tested NF-kB inhibitors, each with different mode of action, potentiated the effect of APR-246 in inhibition of cell viability in HEY-CTLshRNA cells (Fig. 4F,G and Supplementary Fig. S4D).”
Quote in the paperSubstantial claim - Findingown data
NF-kB-driven promoter activity is significantly reduced in HEY-CIP2AshRNA cells compared with controls.
“Further, HEY-CIP2AshRNA cells displayed significantly lower NF-kB-driven gene promoter activity (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
Ovarian cancer cells derived from MISIIR-TAg X CIP2AHOZ mice are highly sensitive to APR-246 in viability and colony growth tests.
“Fully consistent with human cell results, cells from MISIIR-TAg X CIP2AHOZ mice showed a dramatic hypersensitivity to APR-246 both in cell viability and colony growth assays (Fig. 2F,G).”
Quote in the paperSubstantial claim - Findingown data
Cisplatin, paclitaxel, and doxorubicin, which also induce ROS, showed greater potency in CIP2A-deficient cells.
“Although, APR-246 had the greatest CIP2A-dependent effect, other ROS-inducing drugs such as cisplatin, paclitaxel and doxorubicin also had increased potency in CIP2A-deficient cells (Fig 1A).”
Quote in the paperNot a substantial claim - Interpretationown data
Rare CIP2A-positive cells within HEY-CIP2AshRNA tumors gain a strong survival advantage during APR-246 therapy.
“These results indicate that the CIP2A positivity in the rare population of HEY-CIP2AshRNA cells provided a strong selection advantage against APR-246 therapy.”
Quote in the paperSubstantial claim - Interpretationown data
Low-CIP2A ovarian tumors form a small but clinically meaningful human disease subtype.
“Together with our analysis from a limited number of available human relapse samples, these data indicate that OvCa tumors with low CIP2A expression constitute a minor, but yet clinically relevant human OvCa subtype.”
Quote in the paperSubstantial claim- Rests on an assumption: The limited number of relapsed ascites samples (n=10) is representative of relapsed high-grade serous ovarian cancer.
- Interpretationown data
Reduced NF-kB activity is the mechanism by which CIP2A-depleted ovarian cancer cells become sensitive to APR-246.
“These results indicate that inhibition of NF-kB activity mediates APR-246 sensitivity in CIP2A depleted OvCa cells (Fig. 4J).”
Quote in the paperSubstantial claim - Interpretationown data
Low CIP2A expression marks a sensitivity to APR-246 in several chemotherapy-resistant ovarian cancer cell lines.
“Collectively, these results identify low CIP2A expression as a vulnerability to ARP-246 across multiple chemotherapy resistant OvCa cell lines.”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A drives resistance to APR-246 therapy.
“It is dispensable for both human and mouse OvCa tumorigenesis, but associates with more aggressive disease (8)(Supplementary Table S1), and drives resistance to APR-246 therapy.”
Quote in the paperSubstantial claim - Interpretationown data
In vivo, ovarian tumors lacking CIP2A are highly responsive to APR-246.
“These results show that OvCa tumors with low CIP2A expression are hypersensitive to APR-246 therapy in vivo.”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A acts downstream of activated MEKK3 to promote NF-kB activity.
“These findings together with CIP2A effects on p65 phosphorylation (Fig. 4C,D), support the conclusions that CIP2A promotes NF-kB activity downstream of activated MEKK3.”
Quote in the paperSubstantial claim - Interpretationown data
Normal cells from CIP2A-deficient mice do not show a critically limiting APR-246 hypersensitivity, as judged by comparable mouse and organ weights.
“Finally, we did not observe any apparent genotype-specific differences in the weight of the mice or organs from the APR-246 treated mice, indicating that CIP2A deficiency does not result in critically limiting APR-246 hypersensitivity in the normal cells (Supplementary Fig. S3A-D).”
Quote in the paperSubstantial claim - Interpretationown data
CIP2A is a potential target for combination therapy with APR-246 in ovarian cancer.
“Results also reveal CIP2A as a candidate APR-246 combination therapy target for ovarian cancer.”
- Also stated in: § Discussion · plain
“Finally, our results position PP2A inhibitor protein CIP2A as an APR-246 combination therapy target in ovarian cancer.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Interpretationreasoning
In CIP2A-deficient ovarian tumors, TP53 status is unlikely to determine APR-246's cell-killing effect.
“This is a potentially clinically important finding as it indicates that the TP53 status would not dictate the cell killing activity of APR-246 in CIP2A-deficient OvCa subtype tumors.”
Quote in the paperSubstantial claim - Interpretationown data
Some ovarian tumors can develop without CIP2A.
“These results indicate that a portion of OvCa tumors develop in a CIP2A-independent manner.”
Quote in the paperSubstantial claim
- Probably not a substantial claim. 7
- It may state two separate claims as one. 16
- The quote only partly states this claim. 3
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAPR-246 kills cancer cells via multiple mechanisms.
“Current data indicate that APR-246 kills cancer cells via multiple mechanisms (20,21,24–26).”
Quote in the paperNot a substantial claim4 of 5 sources checked- cites [20] Perdrix, 2017, PRIMA-1 and PRIMA-1(Met) (APR-246): from mutant/wild type p53 reactivation to unexpected mechanisms underlying their potent anti-tumor effect in combinatorial therapies, Cancers source
- cites [21] Ceder, 2021, A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death, EMBO Mol Med source
- cites [24] Lambert, 2009, PRIMA-1 reactivates mutant p53 by covalent binding to the core domain, Cancer Cell source
- cites [25] Yoshikawa, 2016, PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells, Oncol Rep source
- cites [26] Tessoulin, 2019, Targeting oxidative stress with auranofin or prima-1(Met) to circumvent p53 or bax/bak deficiency in myeloma cells, Front Oncol source
It may state two separate claims as one.
InterpretationcitationCIP2A is dispensable for both human and mouse ovarian cancer tumorigenesis.
“It is dispensable for both human and mouse OvCa tumorigenesis, but associates with more aggressive disease (8)(Supplementary Table S1), and drives resistance to APR-246 therapy.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Bockelman, 2011, Prognostic role of CIP2A expression in serous ovarian cancer, Br J Cancer source
The paper’s Discussion reports that cytoplasmic CIP2A positivity is associated with aggressive characteristics in human serous ovarian cancer. It does not establish whether CIP2A is dispensable for tumorigenesis in humans or mice; the passages on ovarian cancer cell lines and clinical associations do not test that claim. (LLM, conf=0.76)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataIn a drug screen comparing HEY control and CIP2A-silenced cells, APR-246 was the most apparent sensitizer, reducing viability by more than 50% in CIP2A-silenced cells while control cells were practically insensitive.
“The most apparent sensitization effect was observed with APR-246 (PRIMA-1Met/Eprenetapopt) (15,19–22). Whereas HEY-CTLshRNA cells were practically insensitive to APR-246, HEY-CIP2AshRNA cells showed a >50% reduction in cell viability (Fig. 1A).”
Quote in the paperSubstantial claim4 of 5 sources checked- cites [15] Bykov, 2005, PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis, Oncogene source
- cites [19] Fransson, 2016, Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant high-grade serous ovarian cancer, J Ovarian Res source
- cites [20] Perdrix, 2017, PRIMA-1 and PRIMA-1(Met) (APR-246): from mutant/wild type p53 reactivation to unexpected mechanisms underlying their potent anti-tumor effect in combinatorial therapies, Cancers source
- cites [21] Ceder, 2021, A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death, EMBO Mol Med source
- cites [22] Cluzeau, 2021, Eprenetapopt plus azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia: a phase ii study by the groupe francophone des myelodysplasies (GFM), J Clin Oncol source
It may state two separate claims as one.
InterpretationcitationAPR-246 kills CIP2A-deficient ovarian cancer cells mainly through ROS induction, probably independently of TP53.
“Our data on the ROS-dependent, but most likely TP53-independent mechanism of OvCa cell killing by APR-246 is directly supported by recently published work (21,25).”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [21] Ceder, 2021, A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death, EMBO Mol Med source
The Introduction says APR-246 has pro-oxidant effects and that its redox effects are important for antitumor activity; the results also report growth suppression in ovarian cancer cell lines. But the paper does not study CIP2A-deficient cells or establish that ROS is the main cause of their death. The Discussion says separating redox effects from mutant-p53 effects is difficult, and the results report reduced APR-246 growth suppression after mutant-p53 knockdown, so it does not directly establish TP53 independence. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [25] Yoshikawa, 2016, PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells, Oncol Rep source
It may state two separate claims as one.
PremisecitationPatients whose tumors lack CIP2A, about 17-32% of ovarian cancer cases, show significantly longer cancer-specific survival overall and after platinum-based chemotherapy.
“The remaining 17-32% of OvCa patients with CIP2A-deficient tumors have significantly longer overall cancer-specific survival both in an unselected patient population, as well as among patients treated with standard platinum-based chemotherapy (8).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [8] Bockelman, 2011, Prognostic role of CIP2A expression in serous ovarian cancer, Br J Cancer source
The Results (Immunohistochemistry and Survival analyses; page numbers not supplied) report that 17.2% of serous ovarian cancer specimens were cytoplasmic CIP2A-negative and that these patients had significantly better cancer-specific survival, including in platinum-treated subgroups. The paper does not establish a 17–32% range or extend that prevalence and survival finding to all ovarian cancer types. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCIP2A is linked to stemness traits in patient-derived high-grade serous cancer cells.
“CIP2A was recently also shown in cell culture to protect OvCa cells from Cisplatin-induced apoptosis (10), and to associate with stemness features in patient-derived high grade serous cancer (HGSC) cells (11).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] Kaipio, 2020, ALDH1A1-related stemness in high-grade serous ovarian cancer is a negative prognostic indicator but potentially targetable by EGFR/mTOR-PI3K/aurora kinase inhibitors, J Pathol source
It may state two separate claims as one.
PremisecitationIn high-grade serous ovarian cancer, high CIP2A expression is linked to greater proliferation, aneuploidy, higher tumor grade, TP53 mutation, and EGFR expression.
“High CIP2A expression has been observed in 68-83% of high-grade serous OvCa tumors, and this associates with high proliferation index, aneuploidy, advanced tumor grade, TP53 mutation, and EGFR expression (8,9).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [8] Bockelman, 2011, Prognostic role of CIP2A expression in serous ovarian cancer, Br J Cancer source
The Results (Association to clinicopathological variables and biomarkers; page unavailable) link cytoplasmic CIP2A positivity with high grade, high proliferation index, aneuploidy, aberrant p53 immunoreactivity, and EGFR overexpression. They do not establish an association with TP53 mutation: the measured marker was p53 immunoreactivity. The reported associations and the approximately 83% overall positivity rate concern serous ovarian cancer specimens, not specifically the high-grade subgroup. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [9] Fang, 2012, CIP2A is overexpressed in human ovarian cancer and regulates cell proliferation and apoptosis, Tumor Biology source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAPR-246 needs high micromolar concentrations to kill ovarian cancer cells, matching prior reports and reflecting its conversion to methylene quinuclidinone.
“Of a note, the high micromolar concentrations of APR-246 required for OvCa cell killing is consistent with published studies (21,25), and due to intracellular metabolism of the drug to the active product methylene quinuclidinone (MQ)(21).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [21] Ceder, 2021, A thiol-bound drug reservoir enhances APR-246-induced mutant p53 tumor cell death, EMBO Mol Med source
The Introduction says APR-246 is converted to active methylene quinuclidinone (MQ), and the MRP1-inhibition results report APR-246 growth-suppression experiments in ovarian cancer cell lines. The IC50 analysis describes testing at micromolar concentrations, but the paper does not establish that conversion to MQ is why high concentrations are required for cell killing. Page numbers were not available in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [25] Yoshikawa, 2016, PRIMA-1MET induces apoptosis through accumulation of intracellular reactive oxygen species irrespective of p53 status and chemo-sensitivity in epithelial ovarian cancer cells, Oncol Rep source
The Results report that PRIMA-1MET reduced ovarian cancer cell viability at IC50 values of 2.6–20.1 µM, so the paper supports micromolar activity but not a general requirement for high micromolar concentrations. The Discussion says PRIMA-1MET is converted to methylene quinuclidinone (MQ), but does not say that conversion explains the concentrations needed for cell killing. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataAPR-246 induces ROS production in HEY cells, and this is quenched by NAC pre-treatment.
“In a similar vein, we observed APR-246-elicited induction of ROS production in HEY cells, and this was completely quenched by pre-treatment of cells with antioxidant N-acetyl cysteine (NAC) (Supplementary Fig. S2A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataOverexpressing MEKK3 strongly activates NF-kB promoter activity in HEY control cells, but this activation is reduced in HEY-CIP2AshRNA cells.
“MEKK3 overexpression strongly induced NF-kB promoter activity in HEY-CTLshRNA cells, but this was blunted in HEY-CIP2AshRNA cells (Fig. 4E; lane 3 vs. 4).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataCIP2A shRNA does not impact HEY xenograft tumor growth; if anything, CIP2A-silenced cells grew slightly larger.
“The tumor growth of HEY cells was not impacted by CIP2A shRNA, or if anything, the HEY-CIP2AshRNA grew slightly larger during the follow-up period (Fig. 2A,B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAPR-246 was the only drug in a caspase3/7 apoptosis assay that did not induce apoptosis in HEY control cells but induced a higher apoptotic response in HEY-CIP2A-silenced cells.
“Notably, APR-246 was the only drug that did not induce apoptosis in HEY-CTLshRNA cells but showed clearly higher apoptotic response in HEY-CIP2AshRNA cells (Fig. 1B).”
Quote in the paperSubstantial claimIt may state two separate claims as one. The quote only partly states this claim.
Findingown dataAPR-246 treatment significantly reduced growth of HEY-CIP2AshRNA xenograft tumors, while control xenografts were unaffected.
“Instead, APR-246 therapy significantly decreased tumor growth of HEY-CIP2AshRNA cells (Fig. 2B).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataIn high-grade ovarian cancer tumors at diagnosis, about 22% express CIP2A at low or negative levels.
“We report that 22 % of the high grade OvCa tumors at diagnosis express CIP2A oncoprotein at low levels.”
- Also stated in: § Screening for therapeutics that preferentially kill CIP2A-deficient OvCa cells · plain
“Among this group, 21.4% of tumors had negative CIP2A protein expression (Supplementary Table S1).”
Quote in the paperSubstantial claim- Also stated in: § Screening for therapeutics that preferentially kill CIP2A-deficient OvCa cells · plain
It may state two separate claims as one.
Findingown dataNAC pre-treatment prevents APR-246-elicited killing of CIP2A-silenced cells, supporting ROS induction as a causative mechanism.
“Strongly supporting ROS induction as a causative mechanism for APR-246-elicited killing of CIP2A-silenced cells, NAC pre-treatment prevented the effects of APR-246 in cell viability (Fig. 1E).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataNearly all MISIIR-TAg X CIP2AHOZ tumors were hypersensitive to APR-246, unlike tumors from MISIIR-TAg X CIP2AWT mice.
“After quantification, all but one MISIIR-TAg X CIP2AHOZ tumor showed hypersensitivity to APR-246 therapy, as compared to tumors from MISIIR-TAg X CIP2AWT mice (Fig. 2J).”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Interpretationown dataCIP2A-deficient cells may be hypersensitive to ROS-inducing drugs beyond APR-246.
“Further, based on the initial screening results (Fig. 1A), hypersensitivity of CIP2A-deficient cells to ROS inducing drugs might not be unique to APR-246.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
InterpretationreasoningTumors lacking CIP2A, found in roughly one-fifth of ovarian cancer patients, may define a less aggressive and more treatment-sensitive subtype.
“Together, these results indicate that CIP2A-deficient OvCa tumors, constituting approximately 1/5 of all OvCa patients, may represent a less aggressive, and more therapy sensitive OvCa subtype.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.
Study design and conductown dataAll cell lines used were authenticated by STR profiling and tested negative for mycoplasma.
“All cell lines were authenticated by STR profiling by their respective commercial source or cell line bank.”
- Also stated in: § Cell culture · plain
“The cells were routinely tested for negative mycoplasma contamination according to manufacturer’s protocol (The MycoAlert™ Mycoplasma Detection kit, Lonza).”
Quote in the paperNot a substantial claim- Also stated in: § Cell culture · plain
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataThe human study received ethics committee approval and followed the Declaration of Helsinki.
“The study was approved by the Ethics Committee of the Department of Obstetrics and Gynecology (no 040/95, no 56/13/03/03/2014 §100). The study was conducted according to the principles of Declaration of Helsinki.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataAnimal experiments received approval from the relevant Finnish regional authority.
“All animal work protocols were approved by the Project Authorisation Board of the Regional State Administrative Agency for Southern Finland.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
The retrospective patient cohort and immunohistochemical scoring accurately classify CIP2A tumor status.
“The serous histology of all carcinomas had originally been determined and later verified by a gynecological pathologist.”
“for which both the CIP2A status by immunohistochemistry (IHC), and relapse status was known”
The paper relies on this without support.
The MISIIR-TAg mouse model recapitulates human ovarian cancer with respect to CIP2A dependence and APR-246 response.
“TgMISIIR-TAg transgenic mice (14) were crossed with CIP2A genetrap mouse model (6).”
“Consistent with human data that OvCa tumors may develop in a CIP2A-independent manner (Supplementary Table S1)”
The paper relies on this without support.
Preclinical cell line and mouse findings predict clinical response to APR-246 in ovarian cancer patients.
“Collectively, the results warrant consideration of clinical testing of APR-246 for CIP2A-deficient OvCa tumor subtype patients.”
“By these means the presented results could support a better prediction of the potential responders in future ARP-246 clinical trials, and thus establish a future patient stratification strategy for the clinical use of APR-246.”
The paper relies on this without support.
The limited number of relapsed ascites samples (n=10) is representative of relapsed high-grade serous ovarian cancer.
“we surveyed CIP2A protein expression from a limited number (n=10) of available samples from HGSC OvCa ascites at disease relapse.”
“These results indicate that diagnostic identification of CIP2A status in recurrent OvCa tumors could have predictive potential for these patients regarding clinical responsiveness to APR-246 currently in clinical development (22,23).”
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Metadata
- Authors
- Cvrljevic, A. N., Butt, U., Huhtinen, K., Grönroos, T. J., Böckelman, C., Lassus, H., Butzow, R., Haglund, C., Kaipio, K., Arsiola, T., Laajala, T. D., Connolly, D. C., Ristimäki, A., Carpen, O., Pouwels, J., & Westermarck, J.
- Affiliations
- Åbo Akademi University (FI)
- University of Helsinki (FI)
- University of Turku (FI)
- 9Department of Pathology and Applied Tumor Genomics Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
- Fox Chase Cancer Center (US)
- 2Institute of Biomedicine, University of Turku, Turku, Finland.
- Corresponding author
- Westermarck, Jukka
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2022-04-01
- Volume
- 21
- Issue
- 7
- Pages
- 1236-1245
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC9256766
- OpenAlex
- W4225540723
- Cited by
- 5
- References
- 39
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Työväentutkimus Vuosikirja (submittedVersion, other-oa)
- Funders
- NCI (P30 CA006927)
- Topics
- Health Sciences › Medicine › Oncology › Ovarian cancer diagnosis and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- ovarian cancer, CIP2A, APR-246, NF-κB inhibition, drug hypersensitivity, tumor subtypes, recurrent ovarian cancer, combination therapy, targeted therapy
- MeSH terms
- Carcinoma, Ovarian Epithelial, Animals, Autoantigens, Female, Humans, Ovarian Neoplasms, Quinuclidines, NF-kappa B, Cell Line, Tumor, Mice
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