Oncogenes in colorectal cancer- what a stress

KRAS and BRAF oncogenes are mutated in more than 50% of colorectal cancers. BRAF-mutant colorectal cancer (CRC) is a subtype of colorectal cancer (8-10%) characterized by specific molecular features that affect clinical behavior and response to treatment. BRAFV600E-mutant CRCs are often resistant to chemotherapy and targeted therapies. Combinatorial targeting of the (EGFR) BRAF-MAPK pathway developed in recent years has improved overall survival, but poor response and resistance are still common. Both KRAS and BRAF oncogenes induce MAPK signaling, which drives tumor progression but also induces oncogenic stress. Persistent oncogenic stress renders tumor cells particularly dependent on DNA stress response and DNA damage repair mechanisms, opening new therapeutic vulnerabilities.

When CRC cell lines were tested for sensitivity to CHK1/2, MK2 and ATR inhibitors, apoptosis induction following CHK inhibition was preferentially observed in BRAFV600E mutant cells. While investigating the mechanisms underlying a potential therapeutic sensitivity of BRAFmut CRC, we identified several genes that are synthetically lethal to CHK inhibitors, including DNA polymerases, PP2A, but also claspin (CLSPN). CLSPN is a multifunctional protein involved in DNA replication fork control and DNA stress response as a key mediator of the ATR/CHK response. We found that CLSPN, together with other stress-related genes, is more highly expressed in BRAFV600E CRCs compared to KRASmut or BRAF/KRAS/NRASwt tumors, suggesting that BRAFmut CRCs require higher levels of CLSPN to compensate for oncogenic stress. CLSPN knockdown increased the sensitivity of BRAFV600E cell lines to CHK inhibition, but not of KRASmut cells. Transcriptomic responses to CHK inhibition also revealed differences in MAPK overactivity and in TRAIL and NFkB response. Thus, while oncogenic stress is clearly induced by both KRAS and BRAF oncogenes in colorectal cancer, there are fundamental differences in the response of these CRC subtypes to oncogene activation.