Targeted Therapy to β3 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.

Automated summary

Breast cancer bone metastases are commonly incurable, with tumoral integrin β3 expression influenced by the bone microenvironment. High β3 expression is associated with poor outcomes in triple-negative breast cancer patients both before and after chemotherapy. Additionally, the study suggests mTORC1 inhibition combined with docetaxel can enhance the treatment efficacy in bone metastases.