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Efficacious Combination Drug Treatment for Colorectal Cancer that Overcomes Resistance to KRAS G12C Inhibitors

Matsubara, Hiroyuki 京都大学 DOI:10.14989/doctor.k24804

2023.05.23

概要

Colorectal cancer is one of the most common and lethal cancers in
the world, accounting for approximately 1.8 million new cases and
approximately 900,000 deaths per year (1). Although the prognosis of
patients with colorectal cancer has steadily improved during past
decades due to the development of cytotoxic and moleculartargeted drugs, the 5-year survival rate of stage IV patients still remains
less than 20% (2).
Activating mutations in the KRAS gene are the key driver of most
lethal cancers such as pancreatic (86%), colorectal (41%), and lung
(32%) cancers (3). The mutant KRAS protein constitutively activates
several downstream effector pathways, including the MAPK and PI3K
pathways (4). Although direct inhibition of KRAS activity was a longstanding objective for more than 3 decades of research, no such
targeted therapies were discovered. Thus, the KRAS mutants were
thought “undruggable” due to their high affinity to GTP and lack of
accessible drug-binding pockets (5). However, a paradigm of KRAStargeted therapy has evolved through the development of allelespecific covalent inhibitors for KRAS G12C. These inhibitors bind to
the mutant cysteine residue and occupy the switch II region that is
present only in the inactive GDP-bound form of KRAS G12C, which
prevents its reactivation through nucleotide exchange and traps the
oncoprotein in the inactive state (6). ...

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