Recent studies have highlighted a scenario in which, upon prolonged treatment by a highly specific targeted therapy (such as trastuzumab), tumor cells reprogram themselves to develop alternative compensatory pathways to sustain cell proliferation, ultimately leading to drug resistance17,27
. Additionally, pre-existing genetic alterations of the RTK-PI3K–AKT pathway (such as PTEN loss and IGF-1R overexpression) make tumor cells inherently more resistant to trastuzumab7,8,13
. Owing to the heterogeneous nature of tumors, different resistance mechanisms may coexist in the same patient. Thus, targeting one molecule or one resistance mechanism is usually ineffective27
. Targeting multiple altered signaling pathways that confer resistance is warranted. However, targeting multiple pathways by simply combining several US Food and Drug Administration–approved drugs against each pathway may not always be feasible and may cause severe side effects in some patients28
. To develop more effective regimens to overcome drug resistance, we need to further dissect the signaling events in resistant tumors. Identification of the ‘common signaling nodes’ involved in multiple resistance mechanisms may help researchers to rationally design new combinatorial therapies.
SRC interacts with multiple RTKs through its SH2 domain and facilitates RTK-mediated signaling20,29–34
. Small-molecule inhibitors targeting multiple kinases including SRC (such as PP2 and Dasatinib) potentiate the initial efficacy of anti-RTK therapies in naive tumor cells35–37
. A recent study also suggested that SRC activation may contribute to transient trastuzumab resistance induced by TGF-β treatment36
. Here we demonstrate that, in both acquired and de novo
trastuzumab-resistant tumors, SRC has a universal role in mediating multiple resistance pathways including alternative activation of RTK pathways and PTEN deficiency. This places SRC at a common signaling node for trastuzumab resistance (). Thus, we propose that instead of targeting each of the RTK or PI3K-AKT pathway alterations individually, researchers may effectively overcome trastuzumab resistance resulting from multiple mechanisms by inhibiting this common key node. Our data support this new concept. Targeting SRC universally sensitized trastuzumab-resistant cells to trastuzumab treatment and significantly suppressed tumor growth in vivo
in multiple preclinical resistance models (). This new combination strategy warrants further clinical investigation in patients with trastuzumab-resistant tumors having different de novo
or acquired resistance mechanisms. Furthermore, similar strategies may also be applied to overcoming resistance to other RTK-targeting drugs.
Previously, we tested whether we could overcome de novo
trastuzumab resistance conferred by PTEN deficiency by combining trastuzumab with PI3K-AKT pathway inhibitors38
. In our side-by-side comparison of trastuzumab plus SRC inhibitor versus trastuzumab plus AKT inhibitor in vitro
and in vivo
, we observed that combination with the SRC inhibitor saracatinib was more effective in overcoming trastuzumab resistance in both TtzmR and PTEN deficiency models38
. Notably, from a clinical perspective, toxicity is a critical consideration in prescribing further treatment for trastuzumab-resistant patients who have already been heavily treated. The extensively documented side effects of the clinically applied AKT inhibitor triciribine39
may preclude the combination of this drug with trastuzumab in trastuzumab-resistant patients, although this combination showed some efficacy in our TtzmR xenograft model. In contrast, the SRC inhibitor saracatinib is tolerated well in phase 1 and 2 clinical trials25
. Thus, combination with SRC-targeting agents is a clinically more applicable treatment for trastuzumab-resistant patients.
In addition to the AKT pathway40
, SRC also modulates many downstream targets, including focal adhesion kinase41
, signal transducer and activator of transcription-3 (ref. 42
), mitogen-activated protein kinases43,44
, the protein kinase C family45
. These signaling pathways have diverse roles in regulating tumor cell survival47–49
. Combinatorial therapy with trastuzumab and saracatinib could have a broad impact on tumor progression. Particularly, this combination treatment inhibited migration of trastuzumab-resistant cells (Supplementary Fig. 22
), suggesting a potential benefit of this regimen in preventing further metastatic recurrence for patients with metastatic breast cancer.
In conclusion, our studies identified SRC activation as a key convergence point of multiple trastuzumab resistance mechanisms. The combinatorial regimen of SRC inhibitor plus trastuzumab is effective in overcoming various de novo and acquired resistance mechanisms. Our findings may directly impact the clinical management of patients with ERBB2-overexpressing breast cancer.