Abstract
KRAS is frequently mutated in non-small cell lung cancer (NSCLC). However, direct targeting of KRAS has proven to be challenging, and inhibition of KRAS effectors has resulted in limited clinical efficacy. Wee1 kinase is an important regulator of the G2 checkpoint and is overexpressed in various cancers. Inhibition of Wee1 exerts anticancer effects as a monotherapy or in combination with DNA-damaging agents when cancer cells harbor TP53 mutations. However, its role in KRAS-mutant NSCLC, especially as a single agent, has not been explored. Here, we investigate the anticancer potential of Wee1 inhibitor AZD1775 as a monotherapy and uncover a possible cellular context underlying sensitivity to AZD1775. Our data show that treatment with AZD1775 significantly inhibited cell survival, growth, and proliferation of TP53-mutant (TP53MUT) compared to TP53 wild-type (TP53WT) in KRAS-mutant (KRASMUT) NSCLC cells. In KRASMUT/TP53MUT cells, AZD1775 treatment led to DNA damage, a decrease of survival signaling, and cell death by apoptosis. Interestingly, cell death through apoptosis was found to be heavily dependent on specific cellular genetic context, rather than inhibition of Wee1 kinase activity alone. In addition, AZD1775 treatment was well tolerated and displayed single-agent efficacy in a mouse xenograft model. This study provides rationale for inhibiting Wee1 using AZD1775 as a potential anticancer therapy against the TP53MUT subgroup of KRASMUT NSCLC.
Highlights
KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), and activating KRAS mutations predict poor outcome in response to conventional treatment regimens [1,2,3]
These results suggest that AZD1775 is effective as a single agent in a subtype of NSCSL carrying concomitant KRAS and TP53 mutations, regardless of the coexistence of STK11 mutation
Replication stress is a common feature of oncogenedriven NSCLC, which could sensitize cells to checkpoint kinase inhibition by enhancing S phase damage [5, 6, 13]
Summary
KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC), and activating KRAS mutations predict poor outcome in response to conventional treatment regimens [1,2,3]. Targeting KRAS effector pathways has been suggested as a therapeutic alternative, there are no approved targeted therapies for the treatment of KRAS-mutant (KRASMUT) cancers. Oncogenic KRAS expression is frequently associated with increased DNA damage through replicative stress [3, 4]. In response to DNA damage or replication stress, KRAS-driven cancer cells activate G2 checkpoint kinases, such as ATR, Chk, and Wee, which might promote the survival of these cells [3, 5]. G2 checkpoint kinase inhibitors have been suggested as therapeutics for targeting KRAS-driven cancers [6]. The Wee inhibitor AZD1775 was identified as a potential agent for targeting mutant KRAS-expressing cancers [3, 7]
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