Despite recent advances in targeted and immune-therapies, there is an urgent need for new therapeutic
approaches for metastatic non-small cell lung cancer (NSCLC). SH2 domain-containing phosphatase-2
(SHP2), encoded by PTPN11, is a key “positive” signaling component, required for RAS/ERK MAP kinase
activation by receptor tyrosine kinases (RTKs) and cytokine receptors, as well as by oncogenic amplified RTKs
and protein-tyrosine kinase (PTK) fusion proteins. Recently, potent, orally available, highly specific SHP2
inhibitors were developed. These agents inhibit amplified RTK/PTK-fusion-driven cells/tumors and are in
Phase I clinical trials. Our results suggest that SHP2-inhibitors (SHP2-Is) could have a much broader role in
cancer therapy. SHP2-Is block adaptive resistance to MEK inhibitors (MEK-Is) in KRAS-mutant and -WT cells,
acting upstream of guanine nucleotide exchange factors (SOS1/2). Consequently, SHP2-Is have single agent
efficacy against “cycling” KRAS mutants (e.g., KRASG12C), which retain intrinsic GTPase activity. Supported by
extensive Preliminary Data, we hypothesize that SHP2-Is will also enhance the efficacy of newly developed
KRASG12C (G12C) inhibitors in G12C-mutant NSCLC, the effects of MEK-Is in Osimertinib (Osi)-resistant
EGFR- mutant NSCLC, and the effects of Osi in Osi-sensitive EGFR-mutant NSCLC. SHP2 also binds immune
checkpoint receptors, including PD1, might inhibit immune receptor signaling, and has complex effects on
myeloid cells and other cells in the tumor microenvironment (TME). These pleiotropic actions position SHP2
at the nexus of targeted and immune therapies. This MPI application joins experts in SHP2 action (NEEL) and
NSCLC translational biology (WONG) to clarify the utility of SHP2-Is as NSCLC therapeutics. We will: (1) test
combinations of SHP2-Is with covalent RASG12C inhibitors, MEK-Is, and EGFR-inhibitors in KRAS- and
EGFR-mutant NSCLC GEMMs; (2) clarify cell-autonomous and non-autonomous effects of these combinations
using state-of-the art immune assays, drug-resistant tumor cells, immune cell depletion and new, inducible
SHP2-I-resistant GEMMs; and (3) analyze recurrent tumors and perform CRISPR/Cas9 screens to identify the
landscape of resistance to these agents.