PMID- 31289513
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 1792-1074 (Print)
IS  - 1792-1082 (Electronic)
IS  - 1792-1074 (Linking)
VI  - 18
IP  - 1
DP  - 2019 Jul
TI  - Phenotypic characterization of the novel, non-hotspot oncogenic KRAS mutants E31D 
      and E63K.
PG  - 420-432
LID - 10.3892/ol.2019.10325 [doi]
AB  - KRAS proto-oncogene, GTPase (KRAS) functions as a molecular switch at the apex of 
      multiple signaling pathways controlling cell proliferation, differentiation, 
      migration, and survival. Canonical KRAS mutants, such as those in codons 12 and 
      13, produce constitutively active oncoproteins that short-circuit epidermal 
      growth factor receptor (EGFR)-initiated signaling, resulting in dysregulated 
      downstream effectors associated with cellular transformation. Therefore, 
      anti-EGFR therapy provides little to no clinical benefit to patients with 
      activating KRAS mutations. Current genotyping procedures based on canonical 
      mutation detection only account for ~40% of non-responders, highlighting the need 
      to identify additional predictive biomarkers. In the present study, two novel 
      non-hotspot KRAS mutations were functionally characterized in vitro: KRAS E31D 
      was identified from a genetic screen of colorectal cancer specimens at the 
      UP-National Institutes of Health. KRAS E63K is curated in the Catalogue of 
      Somatic Mutations in Cancer database. Similar to the canonical mutants KRAS G12D 
      and KRAS G13D, NIH3T3 cells overexpressing KRAS E31D and KRAS E63K showed altered 
      morphology and were characteristically smaller, rounder, and highly refractile 
      compared with their non-transformed counterparts. Filamentous actin staining also 
      indicated cytoplasmic shrinkage, membrane ruffling, and formation of pseudopod 
      protrusions. Further, they displayed higher proliferative rates and higher 
      migratory rates in scratch wound assays compared with negative controls. These 
      empirical findings suggest the activating impact of the novel KRAS mutations, 
      which may contribute to resistance to anti-EGFR therapy. Complementary studies to 
      elucidate the molecular mechanisms underlying the transforming effect of the rare 
      mutants are required. In parallel, their oncogenic capacity in vivo should also 
      be investigated.
FAU - Angeles, Arlou Kristina J
AU  - Angeles AKJ
AD  - Disease Molecular Biology and Epigenetics Laboratory, National Institute of 
      Molecular Biology and Biotechnology, National Science Complex, University of the 
      Philippines Diliman, Quezon City 1101, Philippines.
FAU - Yu, Ryan Timothy D
AU  - Yu RTD
AD  - Disease Molecular Biology and Epigenetics Laboratory, National Institute of 
      Molecular Biology and Biotechnology, National Science Complex, University of the 
      Philippines Diliman, Quezon City 1101, Philippines.
FAU - Cutiongco-De La Paz, Eva Maria
AU  - Cutiongco-De La Paz EM
AD  - Institute of Human Genetics, National Institutes of Health, University of the 
      Philippines Manila, Manila 1000, Philippines.
AD  - Philippine Genome Center, University of the Philippines System, Quezon City 1101, 
      Philippines.
FAU - Garcia, Reynaldo L
AU  - Garcia RL
AD  - Disease Molecular Biology and Epigenetics Laboratory, National Institute of 
      Molecular Biology and Biotechnology, National Science Complex, University of the 
      Philippines Diliman, Quezon City 1101, Philippines.
AD  - Philippine Genome Center, University of the Philippines System, Quezon City 1101, 
      Philippines.
LA  - eng
PT  - Journal Article
DEP - 20190506
PL  - Greece
TA  - Oncol Lett
JT  - Oncology letters
JID - 101531236
PMC - PMC6540134
OTO - NOTNLM
OT  - GTPase
OT  - KRAS proto-oncogene
OT  - carcinogenesis
OT  - colorectal cancer
OT  - epidermal growth factor receptor pathway
OT  - oncogene
EDAT- 2019/07/11 06:00
MHDA- 2019/07/11 06:01
PMCR- 2019/05/06
CRDT- 2019/07/11 06:00
PHST- 2018/10/20 00:00 [received]
PHST- 2019/04/02 00:00 [accepted]
PHST- 2019/07/11 06:00 [entrez]
PHST- 2019/07/11 06:00 [pubmed]
PHST- 2019/07/11 06:01 [medline]
PHST- 2019/05/06 00:00 [pmc-release]
AID - OL-0-0-10325 [pii]
AID - 10.3892/ol.2019.10325 [doi]
PST - ppublish
SO  - Oncol Lett. 2019 Jul;18(1):420-432. doi: 10.3892/ol.2019.10325. Epub 2019 May 6.