The Unmet Needs in Oncology That Zedoresertib/Lunresertib Targets

The phase 1 MYTHIC trial (NCT04855656) evaluated a first-in-class combination of the WEE1 inhibitor zedoresertib and the PKMYT1 inhibitor lunresertib in patients with advanced solid tumors, specifically targeting tumors harboring CCNE1, FBXW7, and PPP2R1A genomic alterations. These alterations represent a significant area of unmet clinical need in oncology.

Timothy A. Yap, MBBS, PhD, FRCP, a medical oncologist and physician-scientist, as well as the Random Horne, Jr. Endowed Professor for Cancer Research and vice president and head of Clinical Development in the Therapeutics Discovery Division at UT MD Anderson Cancer Center, presented these findings at the 2026 American Association for Cancer Research (AACR) Annual Meeting. Following the meeting, he spoke with CancerNetwork®.

The biological rationale for combining zedoresertib and lunresertib centers on exploiting replication stress within cancer cells. According to Yap, CCNE1 amplification induces high replication stress by driving cells into a premature S phase. The role of FBXW7 as an E3 ubiquitin ligase is also critical; it typically degrades cyclin E1. Inactivating mutations in FBXW7 prevent this degradation, leading to increased cyclin E1 levels and elevated replication stress. Furthermore, hotspot inactivating mutations in PPP2R1A have been identified as additional drivers of this stress mechanism.

Despite the clear oncogenic role of these alterations, there are currently no specific standard-of-care options that target these pathways in malignancies such as ovarian, uterine, bladder, and lung cancers. By pairing zedoresertib and lunresertib, the MYTHIC trial seeks to leverage the synthetic lethality associated with high replication stress to provide a targeted therapeutic option for these patients. This precision medicine approach aims to fill a critical gap in the management of advanced solid tumors harboring these specific genomic drivers.

Transcript:

I had the pleasure of presenting the first data disclosure of the phase I trial of the first-in-class combination of the WEE1 inhibitor called zedoresertib with the PKMYT1 inhibitor called lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, and PPP2R1A genomic alterations. The important point to make about these cancers with these alterations is that they represent critical areas of unmet clinical need. We know that these play a key role. For example, CCNE1amplification induces high replication stress through premature S phase entry, whilst FBXW7 is an E3 ubiquitin ligase and it proteolytically degrades cyclin E1, therefore inactivating FBXW7 mutations increase cyclin E1 levels and replication stress. Then PPP2R1A hotspot inactivating mutations increase replication stress. There are several cancers with these alterations that represent areas of unmet clinical need. but [have] no specific standard of care options that can target these alterations. These include ovarian cancer, uterine cancer, bladder cancer, and different lung cancers as well.

Reference

1. Yap TA, Aggarwal R, Fontana E, et al. First data disclosure of the Phase I trial of the first in class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations. Presented at the 2026 AACR Annual Meeting; April 17-22, 2026; San Diego, CA. Abstract CT022.