Abstract
Dual SRC and MEK blockade stimulates dormant cell apoptosis and reduces breast cancer metastasis.
Major finding: Dual SRC and MEK blockade stimulates dormant cell apoptosis and reduces breast cancer metastasis.
Mechanism: SRC/MEK inhibition induces nuclear p27 and inhibits the proliferative outgrowth of dormant cells.
Impact: This therapeutic combination may decrease metastatic burden and prevent breast cancer recurrence.
Reactivation of proliferation in disseminated dormant tumor cells promotes tumor recurrence and metastatic progression, emphasizing the need to identify therapeutic strategies to eliminate these latent cells. Changes in extracellular matrix proteins, such as the induction of fibrosis via collagen 1 (COL1) deposition, have been shown to stimulate the proliferative outgrowth of quiescent breast cancer cells in a SRC- and ERK1/2-dependent manner, prompting El Touny and colleagues to evaluate the effect of SRC inhibition on breast cancer dormancy and recurrence. SRC depletion or treatment with the SRC family kinase inhibitor AZD0530 (saracatinib) impaired the COL1-driven increase in dormant cell proliferation in three-dimensional cultures and decreased the percentage of proliferative metastatic lesions in COL1-enriched fibrotic lungs, suggesting that SRC blockade promotes sustained quiescence and suppresses the dormant-to-proliferative switch. In support of this idea, AZD0530 also prevented the spontaneous proliferative outgrowth of highly metastatic mouse and human breast cancer cells. The antiproliferative effect of SRC inhibition was mediated in part by upregulation and nuclear accumulation of the cell-cycle inhibitor p27 and induction of G1 arrest in dormant cells. However, SRC inhibition with AZD0530 did not decrease the viability of dormant tumor cells and was not sufficient to trigger reversion of proliferating metastatic lesions to dormancy or regression of established lung metastases. In contrast with single-agent treatment, concomitant suppression of ERK1/2 signaling using the MEK1/2 inhibitor AZD6244 (selumetinib) induced apoptosis and impaired the initiation of proliferation in both dormant and metastatic tumor cell lines, resulting in diminished metastatic lung tumor burden. Together, these results identify dual SRC/MEK blockade as a potential therapeutic strategy to inhibit the proliferative escape of dormant tumor cells and limit tumor recurrence.
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