Tumor suppressor genes 4

RAS/RAF/MEK/ERK pathway
The RAS family of proto-oncogenes (HRAS, KRAS,
and NRAS) are 21-kD plasma membrane-associated
G-proteins that regulate key signal transduction
pathways involved in normal cellular differenti-
ation, proliferation, and survival [104]. Multiple
studies have shown that oncogenic KRAS (e.g.,
KRASV12 mutant) activates cell signaling pathways
important to cellular transformation [105]. As a
result, KRAS abnormalities represent an impor-
tant therapeutic target. RAS mutations (nearly al-
ways KRAS mutations in lung cancer) are found in
15–20% of NSCLCs, especially in adenocarcinomas
(20–30%), but never in SCLCs [26]. The mutations
occur in codons 12, 13, and 61, all of which in-
fluence intrinsic GTPase activity [104]. A number
of drugs that target different aspects of RAS func-
tion and metabolism have been developed and are
currently under clinical investigation [104]. These
include the farnesyl transferase inhibitors tipifarnib
and lonafarnib, which are now being tested in thecombination with cytotoxic drugs in phase III clini-
cal trials [106].
BRAF protein serine/threonine kinase is a down-
stream effecter of the Ras pathway and mutations
of BRAF occur in ∼70%melanoma, but in only 3%
of lung cancers [107–109]. However, for those rare
lung cancers, mutated BRAF protein is a potentially
important and specific therapeutic target. An orally
administered Raf kinase inhibitor, BAY 43-9006 (so-
rafenib), is currently being tested in phase I and
phase II trials in lung cancer [110–111].
Activated BRAF phosphorylates and activates
MEK1 and MEK2, which in turn phosphorylate
and activate ERK1 and ERK2. However, MEK or
ERK gene amplification ormutations have not been
found in lung cancers. Nevertheless, ERK1/ERK2
are constitutively activated in a subset of lung can-
cers and MEK and ERK remain therapeutic tar-
gets for lung cancer treatment using an oral MEK
inhibitor CI-1040 and its derivative PD03255901
[112].