Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

Abstract

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy.

Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non–Small Cell Lung Cancers In Vitro and In Vivo

“…We described a drug combination that was able to sensitize the resistant KRAS-mutant cell lines and also reactivate the RB tumor suppressor pathway leading to increased levels of G 1 -G 0 arrest and apoptosis. Previous reports have shown the diversity of KRAS-mutant NSCLCs and the need to look at these cell lines comprehensively to prevent resistance in treatments (36,37). Approaching signaling pathways in different ways may provide a new opportunity in the treatment and prognosis of KRAS-mutant NSCLCs.…”

“…Cells used for this study were cryopreserved within 6 months of authentication. All cells were cultured in RPMI-1640 (Invitrogen), supplemented with 10% FBS (Invitrogen) and 1% penicillin/streptomycin (Invitrogen) at 37 C in a humidified 5% CO 2 atmosphere. GSK1120212 (trametinib) was provided by GlaxoSmithKline Pharmaceutical.…”

Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth

“…Identification of mutations that synthetically suppress Ras tumor growth could not only broaden our understanding of cancer biology, but could also lead to the discovery of novel therapeutic targets. Indeed, several laboratories have conducted RNA interference (RNAi)-based synthetic suppressor screens in tissue culture settings and have identified important vulnerabilities of oncogenic Ras cells Luo et al, 2009;Sarthy et al, 2007;Scholl et al, 2009;Steckel et al, 2012;Strebhardt and Ullrich, 2006). Additional wholeanimal synthetic suppressor screens could be particularly informative for revealing the role of oncogenic Ras in processes that are important for regulating growth in vivo.…”

Immunohistochemical Loss of LKB1 Is a Biomarker for More Aggressive Biology in KRAS-Mutant Lung Adenocarcinoma

“…Therapeutic efforts at targeting KRAS have focused on inhibition of its intrinsically activated GTPase activity (6,7), the use of farnesyl transferase inhibitors to impair the association of KRAS with the cell membrane where KRAS mediates its action (8)(9)(10), or synthetic lethality by inhibiting targets that impair the function of dependent genes (11)(12)(13). More recently, inhibition of MEK, the immediate downstream effectors of KRAS-mediated signaling, either alone or in combination with chemotherapy, has been evaluated both in preclinical models and in clinical trials (14,15).…”