Abstract A118: Leveraging metabolic restriction in cooperation with SHP2 deficiency to inhibit PDAC
McKinnon Walsh, Austin Eades, Bailey Bye, Mariana Ruckert, Joseph Cesare, Dennis Province, Collin McCoin, John Thyfault, Michael Washburn, Stephanie Byrum, Michael VanSaunAbstract
Background:
SHP2 (Ptpn11) is a tyrosine phosphatase well defined by its role in the MAPK pathway, including modulation of KRAS activity. KRAS is mutated in >90% of Pancreatic Ductal Adenocarcinoma (PDAC), which is the third leading cause of US cancer deaths. Mutant KRAS drives uncontrolled cell proliferation and cancer growth, typically occurring early in cancer development. The oncogenic role of SHP2 in MAPK regulation has been thoroughly investigated, yet a significant gap remains in understanding MAPK independent activities of SHP2 in cancer.
Methods
& Results: SHP2 is overexpressed (PAAD-TCGA vs GTEx), overabundant (CPTAC proteomic data), and active (pY542/Y580; CPTAC/immunohistochemistry) in PDAC versus normal pancreas tissue. Inhibition of SHP2 with SHP099 (SHP2i) reduced in vitro proliferation in both murine KPC or human PDAC cell lines. Interestingly, the anti-proliferative effects of SHP2i were time dependent and correlated with media acidification. We hypothesized that SHP2 loss drove dependence on lactic acid fermentation, thereby reducing metabolic plasticity. We then utilized CRISPR-Cas9 to knockout SHP2(KO) in K8484 (KPC) cells. We compared SHP2i/KO to MEK inhibition (Trametinib) by extracellular flux assays to differentiate metabolic responses. SHP2i/KO reduced respiration consistently across all cell lines, which was not observed with MEKi. We then compared SHP2KO to long-term-MEKi (48h) and control treated KPC cells by TMT-labeled phospho-proteomic analysis; deficiencies were found in the SHP2KO cells in mitochondrial respiratory proteins, among other metabolic enrichments and deficiencies. Immunoprecipitation-Mass Spectrometry revealed 64 potential mitochondrial protein interactors. Subsequent modeling in AlphaFold visualized phosphosites on 19 of the proteins conforming into SHP2’s catalytic site. Next, we generated pancreas specific knockout of SHP2 (Ptpn11 fl/fl ) mice to assess SHP2’s contribution to PDAC progression in KC & KPC mice (Ptf1a or Pdx1 Cre/+ , Kras G12D/+ , ±p53 R172H/+ ). SΔKC or SΔKPC mice were given either chow diet or a Western-style diet to exacerbate tumor growth, yet both diets resulted in a failure to develop tumors. We then assessed tumor growth in orthotopically implanted control or KO cells in mice given a high-sugar diet (35% sucrose) or ketogenic diet (<0.5% carbohydrate), since the KO cells appeared dependent on glucose in vitro. We found a significant reduction in tumor mass in the SHP2KO-Keto group, but no others.
Discussion:
Collectively, these data led us to conclude that while SHP2 has been studied as a contributor to KRAS signaling in PDAC, SHP2’s differential role in respiratory metabolism has yet to be appreciated or thoroughly investigated; restriction of available nutrients in SHP2 deficient tumors could provide a novel therapeutic strategy supplemental to its role in KRAS activity. We plan to further investigate the mechanisms and outcomes of SHP2 and mitochondrial protein interactions in PDAC metabolism.
Citation Format:
McKinnon Walsh, Austin Eades, Bailey Bye, Mariana Ruckert, Joseph Cesare, Dennis Province, Collin McCoin, John Thyfault, Michael Washburn, Stephanie Byrum, Michael VanSaun. Leveraging metabolic restriction in cooperation with SHP2 deficiency to inhibit PDAC [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A118.