A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non‐small cell lung cancer

Wehler, Thomas; Thomas, Michael; Schümann, Christian; Bosch-Barrera, Joaquim; Segarra, Núria; Dickgreber, N; Dalhoff, K; Sebastian, Martin; Jaime, Jesús Corral; Alonso, Miriam; Hynes, Scott M.; Lin, Ji; Hurt, Karla; Lin, Aimee Bence; Calvo, Emiliano; Paz‐Ares, Luis

doi:10.1016/j.lungcan.2017.03.001

Cited by 40 publications

(32 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the first published phase I/II clinical trials, combination therapies were applied with LY2603618/Rabusertib and either Cisplatin and Pemetrexed, or Pemetrexed alone, or Gemcitabine. Despite the combination, acceptable safety was reported in 6 out of 7 studies, and partial responses, stable disease and increased overall survival was achieved in these initial studies 53–59 . Based on our study and data of others 60 , a phase I/II clinical trial with a highly specific Chk1 inhibitor with or without cell cycle enhancing therapy such as Wee1 inhibition may be initiated for recurrent/metastatic HNSCC.…”

Section: Discussionmentioning

confidence: 93%

Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

et al. 2019

View full text Add to dashboard Cite

Head and neck squamous cell carcinomas (HNSCCs) coincide with poor survival rates. The lack of driver oncogenes complicates the development of targeted treatments for HNSCC. Here, we follow-up on two previous genome-wide RNA and microRNA interference screens in HNSCC to cross-examine tumor-specific lethality by targeting ATM , ATR , CHEK1 , or CHEK2 . Our results uncover CHEK1 as the most promising target for HNSCC. CHEK1 expression is essential across a panel of HNSCC cell lines but redundant for growth and survival of untransformed oral keratinocytes and fibroblasts. LY2603618 (Rabusertib), which specifically targets Chk1 kinase, kills HNSCC cells effectively and specifically. Our findings show that HNSCC cells depend on Chk1-mediated signaling to progress through S-phase successfully. Chk1 inhibition coincides with stalled DNA replication, replication fork collapses, and accumulation of DNA damage. We further show that Chk1 inhibition leads to bimodal HNSCC cell killing. In the most sensitive cell lines, apoptosis is induced in S-phase, whereas more resistant cell lines manage to bypass replication-associated apoptosis, but accumulate chromosomal breaks that become lethal in subsequent mitosis. Interestingly, CDK1 expression correlates with treatment outcome. Moreover, sensitivity to Chk1 inhibition requires functional CDK1 and CDK4/6 to drive cell cycle progression, arguing against combining Chk1 inhibitors with CDK inhibitors. In contrast, Wee1 inhibitor Adavosertib progresses the cell cycle and thereby increases lethality to Chk1 inhibition in HNSCC cell lines. We conclude that Chk1 has become a key molecule in HNSCC cell cycle regulation and a very promising therapeutic target. Chk1 inhibition leads to S-phase apoptosis or death in mitosis. We provide a potential efficacy biomarker and combination therapy to follow-up in clinical setting.

show abstract

Section: Discussionmentioning

confidence: 93%

Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

et al. 2019

View full text Add to dashboard Cite

show abstract

“…The incidence of PE is flexible in various studies, thereby we searched the dates about incidence of PE in patients with lung cancer, hoping to summarize an overall incidence of PE. According to the full-text paper screening, forty-one studies consisting of 13 RCTs 12 - 24 , 27 retrospective cohorts 11 , 25 - 50 , 1 prospective cohort 51 had been selected and showed in table 2 .…”

Section: Incidence Of Pe In Lung Cancer Patientsmentioning

confidence: 99%

“…PE is a frequent finding, with an overall incidence of 3.7% (1,172 of 31,294), ranging from 0 to 23.7% in lung cancer patients 11 - 51 . The pooled frequency of PE in RCTs is 2.3% (66 of 2,903), ranging from 1.3% to 21.4% 12 - 24 , of all the highest rate (21.4%) of PE occur in the process of chemotherapy where nab-paclitaxel was used to treat patients with advanced NSCLC who failed first-line chemotherapy 16 followed by 8% in a RCT for the evaluation of pemetrexed plus cisplatin in combination with or without LY2603618 (a selective checkpoint kinase 1 inhibitor) in patients with advanced nonsquamous NSCLC 12 , impling the incidence of PE in various RCTs for lung cancer patients could be high. The PE rate is lower in lung cancer patients only undergoing lung resection (1.6%, 59 of 3,718, range: 0-2.7%) 25 - 27 , 29 , 34 , 37 , 41 , 43 , 45 , 46 than those only receiving nonsurgical therapy (5.0%, 618 of 12,239, range: 1.3%-21.4%) 11 - 21 , 23 , 24 , 28 , 32 , 33 , 36 , 44 , 51 , yet than those receiving comprehensive therapy (surgical and nonsurgical) (2.5%, 279 of 10,962, range: 0-13.3%) 22 , 30 , 35 , 38 , 39 , 47 - 50 .…”

Section: Incidence Of Pe In Lung Cancer Patientsmentioning

confidence: 99%

Lung Cancer and Pulmonary Embolism: What Is the Relationship? A Review

Shang²,

Wang

et al. 2018

J. Cancer

View full text Add to dashboard Cite

Pulmonary embolism (PE) is gradually considered to be the third most common disease in the vascular disease category. Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death among males worldwide. Although initially appearing as distinct entities, lung cancer is a great risk factor for the development of PE. Pulmonary embolism is common in lung cancer patients, with a pooled incidence of 3.7%, and unsuspected pulmonary embolism (UPE) is also non-negligible with a rough rate ranging from 29.4% to 63%. Many risk factors of PE have been detected and could be classified into three categories: lung cancer-related, patient-related, and treatment-related factors. Decreased mean survival time could be significantly observed in lung cancer patients with PE or UPE compared to those only, but suspected PE has higher mortality than UPE. Prophylactic anticoagulant therapy benefit might be highest in patients with stage IV non-small cell lung cancer (NSCLC) or limited small cell lung cancer (SCLC), and heparin seems superior to warfarin for thrombotic prophylaxis. Periodically reassessing the risk-benefit ratio of anticoagulant treatment will be an efficient treatment strategy in lung cancer patients with PE.

show abstract

“…In a phase 3 study for HNSCC the addition of cetuximab to cisplatin-based chemoradiation resulted in considerably more grade 3/4 mucositis and rash and hence higher rates of interruptions in radiation therapy without achieving any clinical benefit ( 8 ). As further examples, combining bevacizumab with concomitant radiotherapy can lead to decreased wound healing ( 163 , 164 ) and, in patients with lung cancer, to fistula formation ( 165 ), and the Chk1 inhibitors LY2603618 and ADZ7762 increased the risk of severe thromboembolic events ( 166 ) and cardiac side effects ( 167 ), respectively, in part when combined with chemotherapy. At present, preclinical data on tumor radiosensitization hardly ever contain thorough in vivo analyses of side effects other than weight loss and inspection of the skin/mucosa in the radiation field.…”

Section: Discussionmentioning

confidence: 99%

Improving the Efficacy of Tumor Radiosensitization Through Combined Molecular Targeting

et al. 2020

View full text Add to dashboard Cite

Chemoradiation, either alone or in combination with surgery or induction chemotherapy, is the current standard of care for most locally advanced solid tumors. Though chemoradiation is usually performed at the maximum tolerated doses of both chemotherapy and radiation, current cure rates are not satisfactory for many tumor entities, since tumor heterogeneity and plasticity result in chemo-and radioresistance. Advances in the understanding of tumor biology, a rapidly growing number of molecular targeting agents and novel technologies enabling the in-depth characterization of individual tumors, have fuelled the hope of entering an era of precision oncology, where each tumor will be treated according to its individual characteristics and weaknesses. At present though, molecular targeting approaches in combination with radiotherapy or chemoradiation have not yet proven to be beneficial over standard chemoradiation treatment in the clinical setting. A promising approach to improve efficacy is the combined usage of two targeting agents in order to inhibit backup pathways or achieve a more complete pathway inhibition. Here we review preclinical attempts to utilize such dual targeting strategies for future tumor radiosensitization.

show abstract

A randomized, phase 2 evaluation of the CHK1 inhibitor, LY2603618, administered in combination with pemetrexed and cisplatin in patients with advanced nonsquamous non‐small cell lung cancer

Cited by 40 publications

References 13 publications

Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

Targeting the cell cycle in head and neck cancer by Chk1 inhibition: a novel concept of bimodal cell death

Lung Cancer and Pulmonary Embolism: What Is the Relationship? A Review

Improving the Efficacy of Tumor Radiosensitization Through Combined Molecular Targeting

Contact Info

Product

Resources

About