Abstract

Breast cancer bone metastases are common and incurable. Tumoral integrin b3 (b3) expression is induced through interaction with the bone microenvironment. Although b3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of b3þ tumor cells in murine bone metastases after docetaxel chemotherapy. b3þ tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples (n ¼ 38). High tumoral b3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral b3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact b3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in b3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this b3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Furthermore, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated avb3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that b3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with avb3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy.

Original languageEnglish
Pages (from-to)1183-1198
Number of pages16
JournalMolecular Cancer Therapeutics
Volume20
Issue number6
DOIs
StatePublished - Jun 2021

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