SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo

Abstract

RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs). Inhibition of the RAS oncoproteins has proven difficult, and attempts to target downstream effectors have been hampered by the activation of compensatory resistance mechanisms. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor-limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.

SHP2 Inhibition Abrogates Adaptive Resistance to KRASG12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors

“…SHP2 is required for full activation of RAS and the RAS/ERK cascade, but whether SHP2 regulates RAS-exchange or RAS-GAP had been unclear. Recently, several groups, including ours, provided strong evidence that SHP2 acts upstream of SOS1/2 to regulate exchange; consequently, SHP2-Is abrogate adaptive resistance to BRAF-or MEK-inhibitors (28,(34)(35)(36)(37). Recent reports (and our unpublished observations; see Results) show that KRAS G12C -mutant cancer cell lines treated with G12C-Is also develop adaptive resistance (22,(38)(39)(40)(41).…”

“…Allosteric SHP2 inhibitors (e.g., SHP099) reduce the activation of KRAS mutants that retain significant intrinsic GTPase activity ("cycling mutants"), most notably, KRAS G12C , and to a lesser extent, KRAS G12D and KRAS G12V (hereafter G12C, G12D, 12V) in cancer cell lines and reconstituted "RAS-less MEFs" (28,(34)(35)(36)(37). As G12C is impervious to RAS-GAPs (8), these and other data established that SHP2 acts upstream of SOS1/2.…”

Targeting Defects in the Cellular DNA Damage Response for the Treatment of Pancreatic Ductal Adenocarcinoma

“…These combination regimens have shown promising activity in preclinical models and are currently being evaluated in different clinical trials [63]. More recently, 3 studies provided compelling evidence suggesting that SHP2 inhibitors can overcome the adaptive response of KRAS -altered cancer cells to MEK inhibition [64,65,66]. These data pave the way for the clinical evaluation of combinations consisting of inhibitors of MEK and SHP2 for the treatment of KRAS -driven malignancies.…”

“…First, more than 90% of PDAC cases are driven by oncogenic mutations affecting KRAS . While direct targeting of oncogenically mutated KRAS is still in its infancy [54,55], several approaches to indirectly target oncogenic KRAS, including combined CHK1/MAPKAP-K2 inhibition, CHK1 inhibition in combination with genotoxic chemotherapy, combined MEK/PI3K or combined MEK/SHP2 inhibition, have recently emerged and await clinical validation [60,61,62,64,65,66,68,71]. Second, a sizable fraction of PDAC cases harbor germline mutations in a number of DNA repair genes, particularly those involved in DSB repair [13,14,15,16,17,18,19,20,21,22,23].…”

Shipping Out MEK Inhibitor Resistance with SHP2 Inhibitors

“…This is an extremely important fi nding, with translational implications. Patients with cancer who are homozygous for codon 61 RAS mutations (such as Q61R) will likely be refractory to MEK/SHP2 dual-inhibitory therapy, because this mutant has the lowest intrinsic GTPase activity ( 6,8 and colleagues and Wong and colleagues show that SHP2 acts upstream of the RAS-GEF SOS. Expression of the SOS catalytic domain rescues SHP2 inhibition, and depletion of SOS1 and the related protein, SOS2, phenocopies the effect of the SHP2 inhibitor.…”