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KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis
Dana Rabara1, Timothy H Tran1, Srisathiyanarayanan Dharmaiah1
1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21701.
Abstract:
KRAS mutations occur in ∼35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway. KRAS mutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and render KRAS-mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here that KRAS G13-mutated cancer cells are frequently comutated with NF1 GAP but NF1 is rarely mutated in cancers with KRAS codon 12 or 61 mutations. Neurofibromin protein (encoded by the NF1 gene) hydrolyzes GTP directly in complex with KRAS G13D, and KRAS G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Structures of the wild type and G13D mutant of KRAS in complex with neurofibromin (RasGAP domain) provide the structural basis for neurofibromin-mediated GTP hydrolysis. These results reveal that KRAS G13D is responsive to neurofibromin-stimulated hydrolysis and suggest that a subset of KRAS G13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.
Insights
KRAS G13 mutations in colorectal cancer can be responsive to EGFR inhibitors if the tumor has functional neurofibromin. This finding suggests a new therapeutic strategy for a subset of KRAS-mutated cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- KRAS mutations are common in colorectal cancer, driving tumor growth via the MAPK pathway.
- KRAS mutations at codons 12, 13, or 61 typically lead to resistance against EGFR inhibitors.
- The role of NF1 in KRAS G13-mutated cancers and EGFR inhibitor response is not fully understood.
Purpose of the Study:
- To investigate the interplay between KRAS G13 mutations, NF1, and response to EGFR inhibitors in colorectal cancer.
- To elucidate the structural and functional mechanisms of neurofibromin-mediated GTP hydrolysis in KRAS G13D.
Main Methods:
- Analysis of KRAS and NF1 mutation co-occurrence in colorectal cancer datasets.
- Biochemical assays to assess GTP hydrolysis by neurofibromin in complex with KRAS G13D.
- Structural biology studies of KRAS-neurofibromin complexes.
Main Results:
- KRAS G13-mutated colorectal cancers frequently exhibit NF1 co-mutations, unlike cancers with KRAS codon 12 or 61 mutations.
- Neurofibromin directly hydrolyzes GTP in complex with KRAS G13D.
- KRAS G13D-mutated cancer cells demonstrate EGFR inhibitor sensitivity dependent on neurofibromin function.
- Structural data reveals the mechanism of neurofibromin-mediated GTP hydrolysis for KRAS G13D.
Conclusions:
- KRAS G13D is responsive to neurofibromin-stimulated GTP hydrolysis.
- A subset of KRAS G13-mutated colorectal cancers with functional neurofibromin may benefit from EGFR therapies.
- This study provides a mechanistic basis for predicting EGFR inhibitor response in specific KRAS-mutated colorectal cancers.
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