The KRAS p.Ala146Thr mutation promotes the proliferation of colorectal cancer cells via CDK1-mediated ERK signaling

KRAS is the most frequently mutant human oncogene, with mutations present in more than 30% of colorectal cancer (CRC) cases. A rare somatic mutation in KRAS, NM_004985.5 : c.436G>A (p.Ala146Thr), was identified in carcinoma tissues from two CRC patients using Sanger sequencing. An alternative transcript of CDC37 was identified that retained intron 3. No splicing variant was detected within the coding exons and exon-intron boundaries of CDC37. The transcript encoded both truncated and full-length CDC37 proteins. Furthermore, KRAS, CDC37 and HSP90 interacted with each other. The expression levels of HSP90 and CDC37 in carcinoma tissues with the KRAS p.Ala146Thr mutation were higher than those in para-carcinoma tissues. Notably, the p.Ala146Thr mutation significantly upregulated the expression of CDK1, which in turn promoted CRC cell proliferation through activation of ERK signaling. These findings uncover a novel molecular mechanism underlying CRC pathogenesis associated with the KRAS p.Ala146Thr mutation and provide potential insights for developing targeted therapies for this subset of CRC.