A new study published in Science Translational Medicine by researchers at The University of Texas MD Anderson Cancer Center, details a therapeutic vulnerability in patients with an aggressive subtype of triple-negative breast cancer. The investigation shows that simultaneous inhibition of ATR and PKMYT1 triggers a type of cell death in Rb1deficient breast cancer models. Using genomic profiling, proteomics and patient-derived xenografts, the researchers found that loss of Retinoblastoma or Rb1 – a checkpoint gene important for normal cell division – disrupts DNA repair processes and forces tumor cells to rely on ATR and PKMYT1 dependent pathways for survival, creating a vulnerability that can be selectively targeted.
Scientists deem this is a breakthrough discovery since Rb1-deficient tumors do not respond to CDK4/6 inhibitors because they depend on Rb1 to regulate cell division. But that same deficiency makes them vulnerable to ATR and PKMYT1 inhibition. By blocking both repair pathways, the treatment overwhelms the cancer cell’s ability to correct DNA errors, leading to catastrophic DNA damage, apoptosis, tumor shrinkage and improved survival in preclinical models. Rb1 normally prevents uncontrolled cell division and helps maintain genomic integrity. When Rb1 is lost, cells accumulate DNA errors more rapidly and become prone to malignant transformation. These tumors resist CDK4/6 inhibitors because the therapy depends on an intact Rb1 pathway to halt the cell cycle.
The same mechanism that allows mutations to more easily occur also creates the vulnerability. While DNA mutations can lead to cancer development, cancer cells also need to replicate, and if they build too many mutations as they replicate, they can no longer function. Using an inhibitor to intentionally cause this to happen is what’s known as synthetic lethality. By inhibiting ATR and PKMYT1 strategy causes and overload of mutations, leading to cell death and ultimately tumor shrinkage. In this study, targeting these pathways led to tumor shrinkage and increased overall survival in preclinical models. One of the most noteworthy aspects of this study is its near-term clinical relevancy.
Coinhibition of ATR (with camonsertib) and PKMYT1 (with lunresertib) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S-G2 and G2-M checkpoints. This leads to replication stress, premature mitotic entry, and accumulation of DNA damage. Biomarker analysis revealed increased specific histone γH2AX and reduced nuclear Ki67 staining exclusively in Rb1-deficient PDX models, underscoring the specificity of this response. Mechanistically, Rb1 loss impaired double-strand DNA repair by attenuating homologous recombination and nonhomologous end joining (NHEJ). This leads to replication fork collapse, chromosomal instability, and mitotic catastrophe.
Singaling analysis identified JNK/p38 stress response pathway activation as a key driver of apoptosis after ATR/PKMYT1 inhibition. Several ATR and PKMYT1 inhibitors already are in clinical trials and have received fast-track designation from the FDA. The Phase I MYTHIC Trial, which is also being led by MD Anderson researchers, is one example of a trial already testing the combination for certain mutations in solid tumors. The current findings could directly inform the development of Rb1-based biomarker strategies to identify patients most likely to benefit from dual ATR/PKMYT1 inhibition. This same strategy, by the way, is under investigation for gynecological (ovarian and endometrial) cancers.
Xu H et al. (2025) indeed found that low-dose combination of lunsertib with camonsertib synergistically increases cytotoxicity in cyclin E (CCNE1)-amplified compared to non-amplified cells. This combination produces durable antitumor activity, reduces metastasis and increases survival in CCNE1-amplified patient-derived ovary cancer and endometrial cancer xenografts.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Jiang XT et al. Sci Transl Med. 2025; 17(830):eadx6797.
Xu H, George E et al. Nat Commun. 2025; 16(1):3112.
Ngoi NYL et al. Nat Rev Clin Oncol. 2024; 21(4):278-293
Batnini K et al. Int J Mol Sci. 2022 Aug 16; 23(16):9217.
