An optimized S6K inhibitor to overcome limitations of PAM pathway inhibitors
In just over 20 years, protein kinase inhibitors have changed the face of oncology and opened the new eras of targeted therapies and precision medicine. However, with few exceptions, no patient can be cured by one of these drugs alone. Today, scientists seek to develop novel kinase inhibitors with improved efficacy and the potential to overcome resistances. The dual S6K AKT1/3 inhibitor rupitasertib (formerly DIACC3010, acquired from Merck KGaA, Darmstadt, Germany) has both of these characteristics and reaches brain metastases. After successfully completing a Phase I trial in patients with advanced/refractory solid tumors, including breast cancer, the drug candidate will be evaluated in a Phase 2/3 trial in ER+ HER2 breast cancer, which is expected to start in 2024.
The last node of the most important cell signaling routes
The ribosomal protein S6 kinase (also known as S6K) is a serine-threonine protein kinase involved in almost every aspect of tumor cell biology: survival, growth, invasion, metastasis, immune tolerance, drug resistance… Thus, in many cancers (renal cell carcinoma, non-small-cell lung cancer, breast tumors…), the aberrant regulation of S6K is associated with disease aggressiveness and poor patient outcome.
The multifaceted role of S6K in cancer progression
*The EMT, is the physiological process in which epithelial cells gradually acquire the migratory and invasive properties of mesenchymal cells, a critical event in tumor metastasis; **Tumor microenvironment; ***Cancer-Associated Fibroblasts.
In terms of topology, S6K is a downstream node of the PAM signaling cascade, one of the most frequently overactivated pathways in cancer cells. It also interacts with several metabolic nodes, notably the nuclear estrogen receptor (ER), the established driver of 80% of breast cancers.
The S6K-AKT1/3 signaling pathway
The pathway is activated in response to an extracellular signal (growth factor, hormone...…) captured by a receptor of the tyrosine kinase family. Once activated, it triggers a cascade of molecular handshakes from the surface to the cell nucleus where genes will ensure a cellular response in accordance with the signal received (growth, survival...).
PAM inhibitors block tumor progression, but their scope is still limited
To date, PAM inhibitors target upstream nodes of the pathway: PI3K inhibitors (copanlisib, duvelisib, alpelisib), AKT inhibitor (capivasertib) and the mTOR inhibitors (rapamycin (sirolimus) and its analogues (everolimus, and temsirolimus). Overall, these drugs have limited efficacy (notably because they induce multiple feedback loops and compensatory pathways), significant toxicity and their long-term use leads to drug resistance. Still in development, new PAM inhibitors target other isoforms and nodes of the pathway (alone or simultaneously). More selective and less toxic, they could overcome resistance to certain cancer drugs and act in synergy with them.
The unique features of rupitasertib
The mechanism of action of the drug candidate gives it a series of advantages over PAM inhibitors, both in terms of efficacy and safety:
- Rupitasertib interrupts the PAM traffic by inhibiting S6K but it also blocks two of the three AKT isoforms (AKT1 and AKT3), which suppresses any excess activated AKT that result from a compensary feedback loop (the Achilles heel of most PAM inhibitors).
- Rupitasertib spares AKT2 to prevent hyperglycemia, a major adverse effect in patients treated with PAM inhibitors and most likely resulting from AKT2 inhibition.
- Rupitasertib is designed to cross the blood-brain barrier, a rare property among cancer drugs, as illustrated by the very low survival rate of patients with brain metastases.
- Rupitasertib controls the hormone-independent activation of estrogen receptor (ER) a key feature to overcome endocrine therapy resistance in breast cancer patients.
Solid preclinical studies with this compound strongly supported the clinical development of rupitasertib, for which a phase 1 trial has been completed in 101 patients with advanced cancer resistant to multiple standard therapies, including metastatic ER+ HER2- breast cancer patient population with and without ESR1 mutations. Rupitasertib was well tolerated in monotherapy and potential biomarkers of pharmacological activity were seen in peripheral blood mononuclear cells and tumor tissues. Combined with trastuzumab or tamoxifen, rupitasertib also demonstrated early signals of antitumor activity in breast cancer patients.
The drug candidate will be evaluated in a Phase 2/3 trial in ER+ HER2 breast cancer, which is expected to start in 2024.