TY - JOUR
T1 - AXL/WRNIP1 Mediates Replication Stress Response and Promotes Therapy Resistance and Metachronous Metastasis in HER2+ Breast Cancer
AU - Marquez-Palencia, Mauricio
AU - Herrera, Luis Reza
AU - Parida, Pravat Kumar
AU - Ghosh, Suvranil
AU - Kim, Kangsan
AU - Das, Nikitha M.
AU - Gonzalez-Ericsson, Paula I.
AU - Sanders, Melinda E.
AU - Mobley, Bret C.
AU - Diegeler, Sebastian
AU - Aguilera, Todd A.
AU - Peng, Yan
AU - Lewis, Cheryl M.
AU - Arteaga, Carlos L.
AU - Hanker, Ariella B.
AU - Whitehurst, Angelique W.
AU - Lorens, James B.
AU - Brekken, Rolf A.
AU - Davis, Anthony J.
AU - Malladi, Srinivas
N1 - Publisher Copyright:
© 2024 American Association for Cancer Research.
PY - 2024/3/1
Y1 - 2024/3/1
N2 - Therapy resistance and metastatic progression are primary causes of cancer-related mortality. Disseminated tumor cells possess adaptive traits that enable them to reprogramtheir metabolism, maintain stemness, and resist cell death, facilitating their persistence to drive recurrence. The survival of disseminated tumor cells also depends on their ability to modulate replication stress in response to therapy while colonizing inhospitable microenvironments. In this study, we discovered that the nuclear translocation of AXL, a TAM receptor tyrosine kinase, and its interaction withWRNIP1, aDNAreplication stress response factor, promotes the survival of HER2+ breast cancer cells that are resistant to HER2-targeted therapy and metastasize to the brain. In preclinical models, knocking down or pharmacologically inhibiting AXL or WRNIP1 attenuated protection of stalled replication forks. Furthermore, deficiency or inhibition of AXL and WRNIP1 also prolonged metastatic latency and delayed relapse. Together, these findings suggest that targeting the replication stress response, which is a shared adaptive mechanismin therapy-resistant and metastasis-initiating cells, could reduce metachronous metastasis and enhance the response to standard-of-care therapies.
AB - Therapy resistance and metastatic progression are primary causes of cancer-related mortality. Disseminated tumor cells possess adaptive traits that enable them to reprogramtheir metabolism, maintain stemness, and resist cell death, facilitating their persistence to drive recurrence. The survival of disseminated tumor cells also depends on their ability to modulate replication stress in response to therapy while colonizing inhospitable microenvironments. In this study, we discovered that the nuclear translocation of AXL, a TAM receptor tyrosine kinase, and its interaction withWRNIP1, aDNAreplication stress response factor, promotes the survival of HER2+ breast cancer cells that are resistant to HER2-targeted therapy and metastasize to the brain. In preclinical models, knocking down or pharmacologically inhibiting AXL or WRNIP1 attenuated protection of stalled replication forks. Furthermore, deficiency or inhibition of AXL and WRNIP1 also prolonged metastatic latency and delayed relapse. Together, these findings suggest that targeting the replication stress response, which is a shared adaptive mechanismin therapy-resistant and metastasis-initiating cells, could reduce metachronous metastasis and enhance the response to standard-of-care therapies.
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U2 - 10.1158/0008-5472.CAN-23-1459
DO - 10.1158/0008-5472.CAN-23-1459
M3 - Article
C2 - 38190717
AN - SCOPUS:85186960798
SN - 0008-5472
VL - 84
SP - 675
EP - 687
JO - Cancer research
JF - Cancer research
IS - 5
ER -