Targeted Therapy To Beta 3 Integrin Reduces Chemoresistance In Breast Cancer Bone Metastases

Breast cancer bone metastases are common and incurable. Tumoral integrin beta 3 (beta 3) expression is induced through interaction with the bone microenvironment. Although beta 3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of beta 3(+) tumor cells in murine bone metastases after docetaxel chemotherapy. beta 3 thorn tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples (n = 38). High tumoral beta 3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral beta 3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact beta 3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in beta 3-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 beta 3-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 alpha v beta 3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that beta 3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with alpha v beta 3-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.