KRAS: the Achilles’ heel of pancreas cancer biology
Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der
Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der
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Review Series

KRAS: the Achilles’ heel of pancreas cancer biology

Abstract

The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is well-established and dominated by four key genetic driver mutations. Mutational activation of the KRAS oncogene is the initiating genetic event, followed by genetic loss of function of the CDKN2A, TP53, and SMAD4 tumor suppressor genes. Disappointingly, this information has not been leveraged to develop clinically effective targeted therapies for PDAC treatment, where current standards of care remain cocktails of conventional cytotoxic drugs. Nearly all (~95%) PDAC harbors KRAS mutations, and experimental studies have validated the essential role of KRAS mutation in PDAC tumorigenic and metastatic growth. Identified in 1982 as the first gene shown to be aberrantly activated in human cancer, KRAS has been the focus of intensive drug discovery efforts. Widely considered “undruggable,” KRAS has been the elephant in the room for PDAC treatment. This perception was shattered recently with the approval of two KRAS inhibitors for the treatment of KRASG12C-mutant lung and colorectal cancer, fueling hope that KRAS inhibitors will lead to a breakthrough in PDAC therapy. In this Review, we summarize the key role of aberrant KRAS signaling in the biology of pancreatic cancer; provide an overview of past, current, and emerging anti-KRAS treatment strategies; and discuss current challenges that limit the clinical efficacy of directly targeting KRAS for pancreatic cancer treatment.

Authors

Kristina Drizyte-Miller, Taiwo Talabi, Ashwin Somasundaram, Adrienne D. Cox, Channing J. Der

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Figure 2

KRAS GTPase regulation and signaling.

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KRAS GTPase regulation and signaling. (A) KRAS encodes a small GTPase co...
(A) KRAS encodes a small GTPase comprising the G domain and hypervariable region (HVR). Alternative splicing of exon four results in two KRAS isoforms (KRAS4A/KRAS4B, denoted as 4A/B), which differ in their carboxyl-terminal 151–188/189 amino acids. The G domain is involved in guanosine triphosphate (GTP) and guanosine diphosphate (GDP) binding and interactions with guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs), and effectors. HVR contains the CAAX tetrapeptide motif that acts as a signal for posttranslational modifications that promote KRAS plasma membrane association essential for KRAS oncogenic function. Switch I and II regions (denoted as SI and SII) are highlighted, and mutational hot spots at G12, G13, and Q61 positions are indicated with red asterisks. (B) KRAS cycles between active GTP-bound and inactive GDP-bound states. Receptor tyrosine kinase (RTK) signaling promotes GEF-mediated GTP loading and activation of KRAS, which then engages downstream effector signaling (i.e., the RAF/MEK/ERK MAPK cascade). GAPs accelerate intrinsic KRAS GTPase activity and GTP hydrolysis to return KRAS to the inactive GDP-bound state. Amino acid substitutions at G12, G13, and Q61 hot spot positions accelerate GDP to GTP exchange rates and/or impair intrinsic or GAP-induced GTP hydrolysis, resulting in constitutively active KRAS. (C) KRAS undergoes three posttranslational modifications at the carboxyl-terminal CAAX motif (where C denotes cysteine, A denotes aliphatic, and X denotes terminal residues), which is required for association with membranes. Farnesyltransferase (FTase) adds a 15-carbon farnesyl group to the cysteine amino acid at the CAAX motif, RAS-converting enzyme (RCE1) removes -AAX residues, and isoprenylcysteine carboxylmethyltransferase (ICMT) catalyzes carboxylmethylation of farnesylated cysteine. Inhibition of FTase (FTIs) leads to alternative prenylation of KRAS by geranylgeranyltransferase-I (GGTase-I), which adds a 20-carbon geranylgeranyl group and facilitates KRAS associate with membranes. C, cysteine; Ome, carboxyl methylation.