CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models
Summary: CCNE1-amplified ovarian cancers (OVCAs) and endometrial cancers (EMCAs) are associated with platinum resistance and poor survival, representing a clinically unmet need. We hypothesized that dysregulated cell-cycle progression promoted by CCNE1 overexpression would lead to increased sensitiv...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-09-01
|
| Series: | Cell Reports Medicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666379121002524 |
| _version_ | 1819129185683111936 |
|---|---|
| author | Haineng Xu Erin George Yasuto Kinose Hyoung Kim Jennifer B. Shah Jasmine D. Peake Benjamin Ferman Sergey Medvedev Thomas Murtha Carter J. Barger Kyle M. Devins Kurt D’Andrea Bradley Wubbenhorst Lauren E. Schwartz Wei-Ting Hwang Gordon B. Mills Katherine L. Nathanson Adam R. Karpf Ronny Drapkin Eric J. Brown Fiona Simpkins |
| author_facet | Haineng Xu Erin George Yasuto Kinose Hyoung Kim Jennifer B. Shah Jasmine D. Peake Benjamin Ferman Sergey Medvedev Thomas Murtha Carter J. Barger Kyle M. Devins Kurt D’Andrea Bradley Wubbenhorst Lauren E. Schwartz Wei-Ting Hwang Gordon B. Mills Katherine L. Nathanson Adam R. Karpf Ronny Drapkin Eric J. Brown Fiona Simpkins |
| author_sort | Haineng Xu |
| collection | DOAJ |
| description | Summary: CCNE1-amplified ovarian cancers (OVCAs) and endometrial cancers (EMCAs) are associated with platinum resistance and poor survival, representing a clinically unmet need. We hypothesized that dysregulated cell-cycle progression promoted by CCNE1 overexpression would lead to increased sensitivity to low-dose WEE1 inhibition and ataxia telangiectasia and Rad3-related (ATR) inhibition (WEE1i-ATRi), thereby optimizing efficacy and tolerability. The addition of ATRi to WEE1i is required to block feedback activation of ATR signaling mediated by WEE1i. Low-dose WEE1i-ATRi synergistically decreases viability and colony formation and increases replication fork collapse and double-strand breaks (DSBs) in a CCNE1 copy number (CN)-dependent manner. Only upon CCNE1 induction does WEE1i perturb DNA synthesis at S-phase entry, and addition of ATRi increases DSBs during DNA synthesis. Inherent resistance to WEE1i is overcome with WEE1i-ATRi, with notable durable tumor regressions and improved survival in patient-derived xenograft (PDX) models in a CCNE1-level-dependent manner. These studies demonstrate that CCNE1 CN is a clinically tractable biomarker predicting responsiveness to low-dose WEE1i-ATRi for aggressive subsets of OVCAs/EMCAs. |
| first_indexed | 2024-12-22T08:39:42Z |
| format | Article |
| id | doaj.art-317f0b4f67b94645ac9dda7eac42892d |
| institution | Directory Open Access Journal |
| issn | 2666-3791 |
| language | English |
| last_indexed | 2024-12-22T08:39:42Z |
| publishDate | 2021-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports Medicine |
| spelling | doaj.art-317f0b4f67b94645ac9dda7eac42892d2022-12-21T18:32:16ZengElsevierCell Reports Medicine2666-37912021-09-0129100394CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer modelsHaineng Xu0Erin George1Yasuto Kinose2Hyoung Kim3Jennifer B. Shah4Jasmine D. Peake5Benjamin Ferman6Sergey Medvedev7Thomas Murtha8Carter J. Barger9Kyle M. Devins10Kurt D’Andrea11Bradley Wubbenhorst12Lauren E. Schwartz13Wei-Ting Hwang14Gordon B. Mills15Katherine L. Nathanson16Adam R. Karpf17Ronny Drapkin18Eric J. Brown19Fiona Simpkins20Ovarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cancer Biology and the Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAEppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USADepartment of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health & Science University School of Medicine, Portland, OR 97239, USADepartment of Medicine, Division of Translational Medicine and Human Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAEppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USADepartment of Cancer Biology and the Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USAOvarian Cancer Research Center, Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corresponding authorSummary: CCNE1-amplified ovarian cancers (OVCAs) and endometrial cancers (EMCAs) are associated with platinum resistance and poor survival, representing a clinically unmet need. We hypothesized that dysregulated cell-cycle progression promoted by CCNE1 overexpression would lead to increased sensitivity to low-dose WEE1 inhibition and ataxia telangiectasia and Rad3-related (ATR) inhibition (WEE1i-ATRi), thereby optimizing efficacy and tolerability. The addition of ATRi to WEE1i is required to block feedback activation of ATR signaling mediated by WEE1i. Low-dose WEE1i-ATRi synergistically decreases viability and colony formation and increases replication fork collapse and double-strand breaks (DSBs) in a CCNE1 copy number (CN)-dependent manner. Only upon CCNE1 induction does WEE1i perturb DNA synthesis at S-phase entry, and addition of ATRi increases DSBs during DNA synthesis. Inherent resistance to WEE1i is overcome with WEE1i-ATRi, with notable durable tumor regressions and improved survival in patient-derived xenograft (PDX) models in a CCNE1-level-dependent manner. These studies demonstrate that CCNE1 CN is a clinically tractable biomarker predicting responsiveness to low-dose WEE1i-ATRi for aggressive subsets of OVCAs/EMCAs.http://www.sciencedirect.com/science/article/pii/S2666379121002524CCNE1 copy numberWEE1ATRbiomarkerovarian and endometrial cancer |
| spellingShingle | Haineng Xu Erin George Yasuto Kinose Hyoung Kim Jennifer B. Shah Jasmine D. Peake Benjamin Ferman Sergey Medvedev Thomas Murtha Carter J. Barger Kyle M. Devins Kurt D’Andrea Bradley Wubbenhorst Lauren E. Schwartz Wei-Ting Hwang Gordon B. Mills Katherine L. Nathanson Adam R. Karpf Ronny Drapkin Eric J. Brown Fiona Simpkins CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models Cell Reports Medicine CCNE1 copy number WEE1 ATR biomarker ovarian and endometrial cancer |
| title | CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models |
| title_full | CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models |
| title_fullStr | CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models |
| title_full_unstemmed | CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models |
| title_short | CCNE1 copy number is a biomarker for response to combination WEE1-ATR inhibition in ovarian and endometrial cancer models |
| title_sort | ccne1 copy number is a biomarker for response to combination wee1 atr inhibition in ovarian and endometrial cancer models |
| topic | CCNE1 copy number WEE1 ATR biomarker ovarian and endometrial cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2666379121002524 |
| work_keys_str_mv | AT hainengxu ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT eringeorge ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT yasutokinose ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT hyoungkim ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT jenniferbshah ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT jasminedpeake ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT benjaminferman ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT sergeymedvedev ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT thomasmurtha ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT carterjbarger ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT kylemdevins ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT kurtdandrea ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT bradleywubbenhorst ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT laureneschwartz ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT weitinghwang ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT gordonbmills ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT katherinelnathanson ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT adamrkarpf ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT ronnydrapkin ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT ericjbrown ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels AT fionasimpkins ccne1copynumberisabiomarkerforresponsetocombinationwee1atrinhibitioninovarianandendometrialcancermodels |