On January 2th, 2024, TYK Medicines announced that the first patient in the First Affiliated Hospital of USTC (Anhui Provincial Hospital) has been dosed in Phase 1 clinical trial (CTR20233663) of TYK-00540, its novel and highly selective cyclin-dependent kinase 2/4/6 (CDK2/4/6) inhibitor, which is the first patient in China Mainland.

This trial comprises 2 parts, dose escalation and dose expansion, led by Prof. Jian Zhang of Fudan University Shanghai Cancer Center, aiming to evaluate the safety and tolerability of TYK-00540 in patients with advanced/metastatic solid tumors, determine the maximum tolerated dose (MTD), as well the treatment schema, and assess preliminary efficacy.

Dr. Yusheng Wu, the Chairman and CEO of TYK Medicines, said

“We are making every effort to seeking for a novel approach for improving survival and life quality of patients with malignancies. The promising potential has been observed in preclinical studies in terms of anti-tumor efficacy and safety, which prompted us to accelerate the promotion of TYK-00540 into further clinical studies. The enrollment of this patient is the first case of TYK-00540 in China, which can be considered as a milestone.

About CDK2/4/6

Cyclin-dependent kinases (CDKs) are serine/threonine kinases whose catalytic activities are regulated by interactions with cyclins and CDK inhibitors (CKIs). CDKs are key regulatory enzymes involved in cell proliferation via regulating cell-cycle checkpoints and transcriptional processes in response to extracellular and intracellular signals ^[1]. CDKs respond to the extracellular and intracellular signals to regulate cell division, acting as the catalytic subunits. In human cells, there are 20 CDKs and 29 cyclins. CDK1, CDK2, CDK3, CDK4, CDK6 and CDK7 directly regulate cell-cycle transitions and cell division, whereas CDK7-11 mediate gene transcription ^[1].

The clinical studies have demonstrated that CDK4/6 inhibitors outperform conventional medications in the treatment of hormone receptor (HR) positive HER2 receptor negative breast cancer. Although CDK4/6 inhibitors have significantly altered treatment scheme of HR+/HER2- breast cancer, there are still considerable challenges, mainly manifested in primary and acquired CDK4/6 inhibitors resistance ^[2].

The published study showed that when CDK4/6 activity was inhibited, with the expansion of Cyclin E and activation of MYC, CDK2 was upregulated by MYC, and CDK2-CyclinE could be used as a compensatory pathway to phosphorylate Rb and release E2F to promote the proliferation of tumor cells, which is the main mechanism of acquired drug resistance of CDK4/6 inhibitors ^[3]. Overexpression of Cyclin E makes tumor cells resist the inhibitory effect of CDK4/6 and no longer stagnate in the G1 phase ^[4]. Patients with high Cyclin E expression are insensitive to CDK4/6 inhibitors, and their progression-free survival is significantly shorter than that of Cyclin E amplification induced resistance. This mechanism has been confirmed in CDK4/6 resistant cell lines ^[5]. To achieve long-term efficacy, both CDK4 and CDK2 need to be inhibited, which is a new type of treatment that inhibits cancer cells. Simultaneous targeting of CDK2/4/6 is expected to reduce the occurrence of CDK4/6 inhibitory resistance.

Mechanism of CDK4/6 inhibitor resistance

References

[1]. Ding L, Cao J, Lin W, et al. The Roles of Cyclin-Dependent Kinases in Cell-Cycle Progression and Therapeutic Strategies in Human Breast Cancer. Int J Mol Sci. 2020;21(6):1960. Published 2020 Mar 13. doi:10.3390/ijms21061960.

[2]. Goetz MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. J Clin Oncol. 2017;35(32):3638-3646. doi:10.1200/JCO.2017.75.6155.

[3]. Freeman-Cook K, Hoffman RL, Miller N, et al. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. Cancer Cell. 2021;39(10):1404-1421.e11. doi:10.1016/j.ccell.2021.08.009.

[4]. Freeman-Cook KD, Hoffman RL, Behenna DC, et al. Discovery of PF-06873600, a CDK2/4/6 Inhibitor for the Treatment of Cancer. J Med Chem. 2021;64(13):9056-9077. doi:10.1021/acs.jmedchem.1c00159.