Treatment of KRAS-driven cancers is among one of the highest unmet needs in the oncology space. Mutations in KRAS are substantially high in a variety of human tumours, accounting for 90% of pancreatic ductal adenocarcinoma (PDAC), 45% of intestine/colon carcinoma, and 25% of lung adenocarcinoma (ADC).
Scientific research has mainly focused on targeting KRAS itself and downstream effector kinases such as PI3K and MAPK as therapeutic strategies. However, to date there is yet to be an anti-KRAS agent that is approved in oncology and none of the therapies targeting PI3K or MAPK are approved for KRAS-driven cancers, highlighting the shortcomings of the conventional wisdom for treating KRAS-driven cancers and an urgent need to develop more effective therapeutic strategies.
KRAS-driven lung ADC and PDAC mouse models are established research tools that allow scientists to gather insights into the biology of the respective human cancers, test potential therapeutic mechanisms and inform about their feasibility in humans. As reported at the AACR 2018 annual meeting, dual ablation of kinases MEK1 and MEK2 or ERK1 and ERK2 prevent tumour formation in KRAS-driven lung ADC and PDAC models.
However, the functions of these kinases are essential for adult homeostasis and mice do not survive in their absence, indicating that these kinases may not be feasible therapeutic targets in humans with KRAS-driven tumours due to unacceptable toxicity. Consistent with this observation, both Mekinist (trametinib) and selumetinib, two MEK inhibitors, have failed in clinical trials of KRAS-mutant tumours due to excessive toxicity. Although several ERK inhibitors have ongoing clinical trials, similarly, any clinical efficacy due to inhibition of ERK activity is likely to be accompanied by excessive toxicity in patients with KRAS-driven tumours.
On the other hand, ablation of c-RAF, CDK4, or EGFR prevents tumour formation with marginal toxicity in KRAS-driven lung ADC and PDAC models. In more aggressive PDAC models that are driven by both KRAS activation and loss of TP53, another genetic alteration common in human PDAC, individual loss of these kinases delay tumour formation at best, while combined ablation of Egfr and c-Raf activity is tolerable and prevents PDAC formation.
The EGFR inhibitor Tarceva is approved for the treatment of PDAC in combination with gemcitabine, providing negligible clinical benefit to patients. In a similar vein, clinical studies of Raf inhibitors such as regorafenib are evaluating the agent as a monotherapy or in combination with gemcitabine. While mice are not humans, preclinical findings in murine models of human tumours might serve to reveal more potent yet tolerable drug combinations that could improve the lives of many patients with KRAS-driven tumours who at present do not have effective treatment options.
GlobalData (2017). PharmaFocus: Visual Analysis of Immuno-Oncology Development and Opportunities, August 2017, GDHC009PFR.
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