Src is a non-receptor tyrosine kinase that has been associated with carcinogenesis, impairs osteoclast bone resorption, enhances angiogenesis in vivo, and plays a role in the development of breast cancer bone metastases (1-3). Writing in Clinical Breast Cancer, Morris et al. present the results of a single-arm phase II clinical trial evaluating a combination of paclitaxel and dasatinib, a Src inhibitor, in patients with HER2-negative metastatic breast cancer (4). The study was halted early due to slow accrual, but the combination treatment did demonstrate activity in some patients. The objective response rate was 23% and the clinical benefit rate (complete response, partial response, or stable disease) was 43%. The majority of patients (80%) had estrogen-receptor expression, and 68% had bone metastases. Within the cohort, there were a significant percentage of patients that were heavily pre-treated: 30% of patients had received 2 or more lines of endocrine therapy for metastatic breast cancer, 22% of patients had received 2 or more lines of chemotherapy for metastatic breast cancer, and over half of the patients (58%) had previously had treatment with taxanes. There was one patient with triple-negative breast cancer who had a complete response and 7 patients with hormone-receptor positive disease who had partial responses. The investigators did evaluate plasma vascular epidermal growth factor receptor 2 (VEGFR2), plasma N-telopeptide (NTX), and circulating tumor cells as possible biomarkers, but did not identify any correlation between these markers and clinical response.
Interest in Src as a therapeutic target has been evident in the literature for over a decade. Zhang et al. performed a genomic analysis on a large cohort of breast cancer patients and found that a gene expression pattern associated with Src activation was strongly associated with late-onset bone metastases in breast cancer, regardless of breast cancer subtype (5). In addition, Src is an important cross-talk factor between the bone marrow microenvironment and breast cancer cells (5). Specifically, breast cancer cell production of Src leads to osteoclast activation, resorption of bone, and growth of lytic bone metastases through the bone loss (6,7). Preclinical testing of Src inhibitors in breast cancer models has predominantly shown inhibition of bone metastasis formation (1,8); however, in the 4T1 murine mammary carcinoma, dasatinib actually enhanced bone metastasis formation (9).
Overall, the clinical trial data using Src inhibitors in unselected metastatic breast cancer patients has been disappointing (Table 1), but a recent study using Src inhibition in combination with chemotherapy and trastuzumab was more promising and reached an objective response rate of 79% (19). Src activation has been found to be a mechanism of resistance in HER2+ breast cancer (20), and perhaps the combination of Src inhibitors and HER2-targeting therapies is a more promising paradigm. The results of Morris et al. and other trials employing Src inhibitors in HER2− breast cancer populations fail to meet the expected outcomes of better response in patients with bone metastases as well as the triple-negative breast cancer patients established by the pre-clinical studies. It is interesting to note that in Morris et al., on-target biomarkers of Src engagement were no different between responders and non-responders, and as is the case in multiple other trials, the responders are generally hormone-receptor positive.
This leads one to question the role of Src in these patients. Dasatinib is a promiscuous kinase inhibitor and inhibits both the Src tyrosine kinase as well as the ABL tyrosine kinase. It also has effects on the STAT5, c-kit, and platelet-derived growth factor pathways (21). ABL kinase overactivation has been noted in breast cancer cell lines, and has also been found in aromatase-inhibitor resistant breast cancers (22); the PDGFR pathway and c-kit mutations have also been implicated in breast cancer (23).
Although the combination of dasatinib and chemotherapy has in general been lackluster, it is noteworthy that there are two reports of complete responses in the literature with a combination of dasatinib and chemotherapy. One is a recent case report of a patient with simultaneous hormone-receptor positive metastatic breast cancer and chronic myelogenous leukemia (CML) already on dasatinib who developed endocrine therapy-resistance and new liver metastases (24). She received paclitaxel while continuing her dasatinib with stable breast cancer for over a year. At time of liver disease progression, she was switched to vinorelbine + capecitabine with continuation of her dasatinib and achieved a complete response in her visceral disease (stable bone metastases). The other case was presented by Morris et al. in Clinical Breast Cancer: a patient with triple-negative breast cancer with previous taxane-exposure who achieved a complete response with dasatinib and paclitaxel (4).
Exploration of the mechanism of action for these two exceptional responders would be enlightening, as their exquisite response may be related to an alternative pathway inhibited or influenced by dasatinib. For valuable multi-kinase inhibitors such as dasatinib with pleiotropic molecular network interactions, patient-specific functional testing with ex vivo organoids or bespoke patient-derived xenografts may provide a better clue to which breast cancer tumors are most likely to robustly respond.
Funding: Dr. Kennedy’s training is supported by the NCI under award number T32CA009515.
Conflicts of Interest: Dr. Gadi has the following conflicts of interest: SEngine Precision Medicine (ownership and consulting), Novartis (consulting), Pfizer (consulting), Daichii Sankyo (consulting), Seattle Genetics (consulting), and Genentech (research funding). LC Kennedy has no conflicts of interest to declare.
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