SHP2 blockade sensitizes triple negative breast cancers to PI3K inhibition leading to metastatic shrinkage

Breast cancer is the most frequent and lethal cancer among women worldwide. A third of breast cancers can progress to metastasis, which remains the major cause of death in patients with solid tumors. Cells are regulated by numerous interconnected pathways, which can be dysregulated and results in uncontrolled proliferation. The phosphatidylinositol 3-kinase (PI3K) pathway is implicated in cellular growth, proliferation and survival, and is aberrantly activated in 70% of breast cancers. Despite the development of specific and effective drugs targeting the PI3K pathway, most clinical trial outcomes have been disappointing. In fact, mechanisms of resistance can short-circuit the efficacy of such inhibitors. Some of these mechanisms are receptor tyrosine kinase (RTK) driven, activating compensatory pathways and dramatically reducing the initial efficacy.
Downstream of various active RTKs, Src-homology 2 domain-containing phosphatase (SHP2), a ubiquitously expressed protein-tyrosine phosphatase (PTP), transduces mitogenic, survival, cell-fate and/or migratory signals. Blockade of SHP2 has been shown to decrease breast tumor growth, progression and metastasis. Given that RTK-driven signaling pathways can overcome the effects of PI3K inhibition, and that SHP2 enhances signaling downstream of these receptors, we studied the effects of targeting PI3K and SHP2 simultaneously.
In this study, we demonstrate a fundamental effect of PI3K/SHP2 dual-inhibition in triple-negative breast cancers (TNBCs), a very aggressive subtype associated with poor prognosis. Dual inhibition targeting PI3K and SHP2 appears to be more effective than single inhibitions by decreasing cell number in vitro and tumor volume in vivo, as well as increasing cancer cell apoptosis and improving animal survival. Mechanistically, SHP2 inhibition results in activation of the PI3K signaling and dependency on this pathway.
We then assessed the effects of PI3K and/or SHP2 inhibitions on primary tumor growth, animal survival and lung metastases, a major metastatic site in breast cancer. While PI3K inhibition had no effects on primary tumor growth, it resulted in larger lung metastases in the neo-adjuvant setting. SHP2 inhibition decreased primary tumor growth as well as lung metastases. Both PI3K and SHP2 single treatment groups did not improve animal survival. In combination, PI3K/SHP2 dual-inhibition reduced synergistically primary tumor volumes, decreased lung metastases and increased animal survival.
In the adjuvant setting, PI3K and SHP2 single inhibitions, as well as PI3K/SHP2 dual-inhibition, decreased lung metastases and increased animal survival. Despite the lack of lung metastases, concurrent PI3K/SHP2 blockade is not enough for complete metastasis regression. We demonstrated that liver metastases developed in parallel and have revealed to be insensitive to such inhibitions. We highlighted the discrepancy in RTK-dependences with lung metastases being PDGFRβ-dependant, while liver metastases are VEGFRs-dependent. Using a VEGFR/PDGFR inhibitor, we finally indicate that targeting PI3K/SHP2/VEGFR/PDGFR can further improve animal survival.
The observations that pan-PI3K inhibition in the neo-adjuvant setting increases lung metastases in TNBC calls for caution when using such agents in the presence of the primary tumor. We have reported similar results using a dual-PI3K/mTOR inhibitor (Britschgi, Andraos et al. 2012). Our data provide a rationale for using pan-PI3K in combination with SHP2 inhibition to treat metastatic TNBC in the adjuvant setting and support further testing of this possibility. Moreover, we provide evidence that a triple therapy of PI3K, SHP2 and VEGFR/PDGFR inhibitors overcomes niche-dependent resistance and prolongs survival in preclinical models of TNBC.