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Why “pan” Inhibitors?
KRAS mutations can be acquired
● Treatment with G12C inhibitors can lead to acquired
resistance
● In a study on patients under G12C inhibitor treatment for
lung cancer (NCSCLC), colorectal cancer (CRC) and
appendix cancer (AC) that acquired resistance, numerous
acquired mutations were detected (figure on right, and
citation in lower right)
● Mutations at the G12 codon other than “C” would lead to a
failure of G12C inhibitors. Concurrent mutations in switch II
binding pocket (Q, R, H, Y) also affect sotorasib, adagrasib
● Supports need to develop pan-KRAS inhibitors, and drugs
with alternative modes of binding for combo therapy
https://www.nejm.org/doi/10.1056/N
EJMoa2105281
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