Redefining KRAS activation

Oncogenic mutations in KRAS are considered to ‘lock’ the protein in a constitutively active state, which therefore results in ligand-independent activation of KRAS signalling. Two separate preclinical studies now challenge this paradigm, indicating that, in order to drive lung tumorigenesis, mutant KRAS requires the activation of ERBB receptors.
Emilio Casanova and his team found that genetic deletion of Egfr (a member of the ERBB family) reduced the growth of Kras-mutated lung adenocarcinomas in mice. “Previous clinical trials had shown that the EGFR inhibitors erlotinib and gefitinib were not effective in patients with KRAS-mutated lung adenocarcinomas,” explains Casanova, who adds “we confirmed this effect in our experimental model, in which these inhibitors triggered a tumour-escape mechanism. However, the pan-ERBB inhibitor afatinib blocked the escape mechanism leading to impaired lung tumorigenesis.”
In their study, Daniel Murphy and collaborators developed a mouse model combining mutant Kras with a modest overexpression of Myc. “we initially observed low-grade adenocarcinomas that were uniform in appearance, but
6 weeks after tumour initiation, we saw discrete regions with altered histology in individual tumours,” explains Murphy. These regions were isolated, and their transcriptomes were compared with those of low-grade regions, revealing increased expression of multiple ligands from the ERBB family along with other genes that enhance EGFR and/or ERBB signalling. Treatment with the pan-ERBB inhibitor neratinib enhanced the antitumour effect of the MEK inhibitor trametinib in mice harbouring Kras-mutant tumours.
“From the clinical perspective, the most important finding is that
Kras-driven lung tumours are sensitive to ERBB inhibition in mice. These drugs now need to be evaluated in clinical trials. Substantial toxicities will need
to be overcome, likely through lung-restricted delivery of the drugs or biomarker-guided treatment scheduling,” explains Murphy. Likewise, Casanova considers that “a clinical trial with afatinib, an FDA-approved drug, in patients with KRAS-mutated lung adenocarcinoma should be straightforward, although patient stratification based on the presence of biomarkers predicting response to afatinib will likely be needed.”
Comparing both studies, Murphy comments “In our experiments,
no survival benefit was derived from monotherapy with neratinib, whereas Casanova and colleagues report efficacy using a different pan-ERBB inhibitor (afatinib) as a single agent. The difference is likely to be derived from the different dosing schedules or mouse models used.” Casanova adds “we are very excited that we arrived independently at the same conclusion, which makes us very confident of the robustness of these findings.”BIBW2992