Abstract 670: Distinct biochemical properties of KRAS Q61H mutant render cancer cells resistant to SHP2 inhibitors
Bibliographic record
Abstract
Abstract Recent reports suggest that specific KRAS mutations are associated with either resistance or sensitivity of cancer cells to SHP2 inhibitors (SHP2i). However, a lack of understanding of the underlying mechanism(s) is hindering the clinical advancement of SHP2i therapy for cancer. Here we report that cancer cells that harbor KRAS Q61H mutation (found in about 5% of pancreatic ductal adenocarcinoma tumors) or HEK293 cells that over-express KRAS Q61H are resistant to SHP2i. Our biochemical studies supported by all atom molecular dynamic simulations show that the Q61H mutation impairs intrinsic GTP hydrolysis and impedes stimulation of the GTPase cycle by both SOS1 and RASA1, but has negligible impact on binding to BRAF-RBD. Similar to wild-type KRAS, the Q61H mutant can be phosphorylated by Src at Tyr-32 and Tyr-64, and both site scan be dephosphorylated by SHP2, although SHP2i does not reduce ERK phosphorylation in KRAS Q61H cells. In vitro, phosphorylation of KRAS Q61H increased intrinsic nucleotide exchange without affecting its insensitivity to SOS1 and RASA1. Phosphorylation of wild-type and SHP2i-sensitive mutants (e.g., G12V) confers resistance to SOS1/RASA1 activities and impairs binding to BRAF-RBD, thus the constitutive resistance to upstream regulation and uncompromised ability of phosphorylated KRAS Q61H to activate MAPK signaling are distinct properties of this mutant. Decoupling of KRAS Q61H from upstream signaling and impaired intrinsic nucleotide hydrolysis lead to a highly GTP-loaded pool that is insensitive to the suppressive effects of Src phosphorylation. While SHP2 plays multiple roles in stimulating RAS signaling, including promoting the GEF function of SOS1, reducing p120 GAP-mediated inactivation of KRAS, and reversing Src phosphorylation of KRAS, we revealed that none of these are required by KRAS Q61H. These insights provide a mechanistic understanding of oncogenic KRAS mutants that can guide clinical trials of SHP2 inhibitors for patients with pancreatic and other cancers bearing KRAS Q61H. Citation Format: Teklab Gebregiworgis, Yoshihito Kano, Michael Ohh, Christopher B. Marshall, Mitsuhiko Ikura. Distinct biochemical properties of KRAS Q61H mutant render cancer cells resistant to SHP2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 670.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".