WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: A biomarker-enriched phase II study

Embaby, Alaa; Kutzera, Joachim; Geenen, Jill J.J.; Pluim, Dick; Hofland, Ingrid; Sanders, Joyce; López-Yurda, Marta; Beijnen, Jos H.; Huitema, Alwin D. R.; Witteveen, Petronella O.; Steeghs, Neeltje; Haaften, Gijs van; Vugt, Marcel A.T.M. van; Ridder, Jeroen de; Opdam, Frans

doi:10.1016/j.ygyno.2023.05.063

Cited by 10 publications

(10 citation statements)

References 37 publications

(58 reference statements)

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“…The WEE1 inhibitor MK-1775 in combination with carboplatin or gemcitabine hydrochloride was tested in two phase II trials (NCT01164995 and NCT02272790). Adavosertib combined with chemotherapy showed preliminary therapeutic efficacy in platinum-resistant ovarian cancer, but the hematologic toxicity of this combination may limit its application [ 216 , 217 ]. In addition, a phase I/II clinical trial of the WEE1 inhibitor ZN-c3 combined with niraparib was conducted in patients with platinum-resistant ovarian cancer (NCT05198804), but no results have been published.…”

Section: Strategies For Overcoming Drug Resistancementioning

confidence: 99%

Drug resistance in ovarian cancer: from mechanism to clinical trial

Wang,

Zhu

et al. 2024

Mol Cancer

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Ovarian cancer is the leading cause of gynecological cancer-related death. Drug resistance is the bottleneck in ovarian cancer treatment. The increasing use of novel drugs in clinical practice poses challenges for the treatment of drug-resistant ovarian cancer. Continuing to classify drug resistance according to drug type without understanding the underlying mechanisms is unsuitable for current clinical practice. We reviewed the literature regarding various drug resistance mechanisms in ovarian cancer and found that the main resistance mechanisms are as follows: abnormalities in transmembrane transport, alterations in DNA damage repair, dysregulation of cancer-associated signaling pathways, and epigenetic modifications. DNA methylation, histone modifications and noncoding RNA activity, three key classes of epigenetic modifications, constitute pivotal mechanisms of drug resistance. One drug can have multiple resistance mechanisms. Moreover, common chemotherapies and targeted drugs may have cross (overlapping) resistance mechanisms. MicroRNAs (miRNAs) can interfere with and thus regulate the abovementioned pathways. A subclass of miRNAs, “epi-miRNAs”, can modulate epigenetic regulators to impact therapeutic responses. Thus, we also reviewed the regulatory influence of miRNAs on resistance mechanisms. Moreover, we summarized recent phase I/II clinical trials of novel drugs for ovarian cancer based on the abovementioned resistance mechanisms. A multitude of new therapies are under evaluation, and the preliminary results are encouraging. This review provides new insight into the classification of drug resistance mechanisms in ovarian cancer and may facilitate in the successful treatment of resistant ovarian cancer.

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Section: Strategies For Overcoming Drug Resistancementioning

confidence: 99%

Drug resistance in ovarian cancer: from mechanism to clinical trial

Wang,

Zhu

et al. 2024

Mol Cancer

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“…As PKMYT1, but not WEE1, is more important for G2/M transition during checkpoint recovery [207] its inhibitors could be important for a number of combinational therapies aimed at RS. and rhabdomyosarcoma [194,195,[208][209][210][211][212][213][214][215] Phase 1 (34 trials, including 6 terminated and 1 withdrawn) HNSCC, uterine cancers, TNBC, pancreatic cancer, acute myeloid leukemia, glioblastoma [192,193,[216][217][218][219][220][221][222][223][224][225][226][227][228]…”

Section: Wee1 and Pkmyt1 Inhibitorsmentioning

confidence: 99%

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

Khamidullina,

Abramenko,

Bruter

et al. 2024

IJMS

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Replication stress (RS) is a characteristic state of cancer cells as they tend to exchange precision of replication for fast proliferation and increased genomic instability. To overcome the consequences of improper replication control, malignant cells frequently inactivate parts of their DNA damage response (DDR) pathways (the ATM-CHK2-p53 pathway), while relying on other pathways which help to maintain replication fork stability (ATR-CHK1). This creates a dependency on the remaining DDR pathways, vulnerability to further destabilization of replication and synthetic lethality of DDR inhibitors with common oncogenic alterations such as mutations of TP53, RB1, ATM, amplifications of MYC, CCNE1 and others. The response to RS is normally limited by coordination of cell cycle, transcription and replication. Inhibition of WEE1 and PKMYT1 kinases, which prevent unscheduled mitosis entry, leads to fragility of under-replicated sites. Recent evidence also shows that inhibition of Cyclin-dependent kinases (CDKs), such as CDK4/6, CDK2, CDK8/19 and CDK12/13 can contribute to RS through disruption of DNA repair and replication control. Here, we review the main causes of RS in cancers as well as main therapeutic targets—ATR, CHK1, PARP and their inhibitors.

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“…There are authors who have demonstrated that APR-246 was well tolerated with a clinical response and remissions because it was capable of restoring wild-type p53 function in malignant cells administered in combination with azacytidine in patients with TP53-mutant myeloproliferative neoplasms, such as acute myeloid leukaemia (ClinicalTrials.gov identifier: NCT03072043) [110]. In addition, Adavosertib, which is a potent antitumor kinase inhibitor, in combination with carboplatin in advanced TP53 mutated ovarian cancer has been used at phase II (ClinicalTrials.gov identifier: NCT01164995) [111].…”

Section: Tp53 Mutationsmentioning

confidence: 99%

“…APR-246 (Eprenetapop) with carboplatin in advanced Tp53 mutated ovarian cancer at phase II (Clinical Trials.gov. identifier: NCT01164995) [111].…”

Section: Pole Domain Mutationsmentioning

confidence: 99%

Dedifferentiated Endometrial Carcinoma: A Rare Aggressive Neoplasm-Clinical, Morphological and Immunohistochemical Features

Giordano,

Ferioli,

Guareschi

et al. 2023

Cancers

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Dedifferentiated endometrioid adenocarcinoma is characterised by the coexistence of an undifferentiated carcinoma and a low-grade endometrioid adenocarcinoma. The low-grade component in this subtype of endometrial carcinoma is Grade 1 or 2 according to the Federation of Gynaecology and Obstetrics (FIGO) grading system. The coexistence of low-grade endometrial carcinoma and solid undifferentiated carcinoma can cause diagnostic problems on histological examination. In fact, this combination can often be mistaken for a more common Grade 2 or Grade 3 endometrial carcinoma. Therefore, this subtype of uterine carcinoma can often go under-recognised. An accurate diagnosis of dedifferentiated endometrial carcinoma is mandatory because of its poorer prognosis compared to Grade 3 endometrial carcinoma, with a solid undifferentiated component that can amount to as much as 20% of the entire tumour. The aim of this review is to provide clinical, immunohistochemical, and molecular data to aid with making an accurate histological diagnosis and to establish whether there are any findings which could have an impact on the prognosis or therapeutic implications of this rare and aggressive uterine neoplasm.

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WEE1 inhibitor adavosertib in combination with carboplatin in advanced TP53 mutated ovarian cancer: A biomarker-enriched phase II study

Cited by 10 publications

References 37 publications

Drug resistance in ovarian cancer: from mechanism to clinical trial

Drug resistance in ovarian cancer: from mechanism to clinical trial

Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets

Dedifferentiated Endometrial Carcinoma: A Rare Aggressive Neoplasm-Clinical, Morphological and Immunohistochemical Features

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