Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling

Abstract

Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development. Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined. Results: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody. Conclusions: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.

Mechanisms of Resistance to KRASG12C Inhibitors

“…In agreement with these findings, the SHP2 inhibitor TNO155 has been shown to overcome feedback reactivation of RTK signalling induced by G12C inhibition and was found to act synergistically with the G12C inhibitor Cpd 12a to inhibit proliferation in KRAS G12C cell lines. This synergistic effect was the most significant of all TNO155 combinations tested in the study and was also postulated to be secondary to increased GDP occupancy of KRAS [ 66 ]. Taken together, this evidence suggests that SHP2 may prove to be a useful target to overcome KRAS G12C inhibitor resistance.…”

SHP2 Inhibition as a Promising Anti-cancer Therapy: Function in Tumor Cell Signaling and Immune Modulation

“…These findings raise the possibility that SHP2 inhibition relieves T cell suppression largely through reduction of M2 macrophages via CSF1R signaling, and partially through PD-1 signaling, where SHP2 appears dispensable due to functionally redundant mechanisms. Interestingly, despite modest effect of PD-1 blockade on M2 TAM, further reduction of M2 macrophages is elicited with combined SHP2i and PD-1 blockade through an undefined mechanism [26,50], which may be the potential basis for additive anti-tumor activity of combined SHP2i and anti-PD-1. Furthermore, combined SHP2i and anti-PD-1 treatment also demonstrates synergistic effects on colon cancer models that are sensitive to checkpoint blockade [49,50].…”

“…SHP2 inhibition offers a promising therapeutic strategy as a means to prevent RTK-driven adaptive and acquired resistance to targeted therapy. SHP2 inhibition enhances the efficacy of tyrosine kinase inhibitors (TKI), such as ALK/EGFR/FGFR inhibitors, in drug-resistant NSCLC and metastatic breast cancer, in which distinct RTK activation mediates adaptive and acquired resistance [25][26][27][28]. In addition, SHP2 inhibition (or depletion) also restores sensitivity to ERK signaling inhibition and has additive/synergistic anti-tumor effects when combined with KRAS G12C /RAF/MEK inhibitors in multiple models of cancers driven by hyperactivated RAS, including KRASmutant pancreatic, lung and colorectal cancers, KRAS WTamplified gastroesophageal cancer, RAS WT triple negative breast cancer (TNBC) and ovarian cancers, NRAS-mutant neuroblastoma, NF1-deficient MPNST, and BRAF-mutant colon and thyroid cancers, among others, through blocking signal transduction from most RTK that are reactivated through loss of negative feedback following ERK pathway inhibition [19,24,26,[29][30][31][32][33][34][35][36][37][38].…”

“…SHP2 inhibition provokes increases in intratumoral CD8+ T-lymphocytes and tumor-associated B-lymphocytes, augmenting anti-tumor immunity [38,49]. Recent findings have emerged regarding the role of SHP2 in modulating the myeloid compartment as well [26,38,50]. Myeloid cells are the most abundant white blood cells in the human body and they are present practically in all tissues.…”

“…M2 macrophages exhibit potent T-cell suppressive phenotypes in vitro and in vivo [52,58,59]. SHP2 inhibition in RASdriven cancers results in depletion of immunosuppressive M2 macrophages through attenuation of CSF1R signaling [26,50], which is essential for T-cell suppression by immunosuppressive TAM [60] within the TME. These findings raise the possibility that SHP2 inhibition relieves T cell suppression largely through reduction of M2 macrophages via CSF1R signaling, and partially through PD-1 signaling, where SHP2 appears dispensable due to functionally redundant mechanisms.…”