Rupitasertib

First-in-class oral double-node PAM pathway inhibitor targeting S6K and AKT1/3 to address resistance to endocrine therapies and CDK2/4/6 inhibitors in breast cancer

Large phase 1 trial (101 patients) was run by Merck KGaA[1]
Favorable safety profile compared to existing PAM inhibitors: low hyperglycemia, minimal discontinuation, broader patient inclusion
Unique potential in combination with SERDs, CDK2/4/6 inhibitors, triplet combination, and additional opportunities in ER+ solid tumors

The ribosomal protein S6 kinase

S6K is a critical downstream effector of the PAM pathway. Activated S6K could promote various aspects of cancer progression[2]
S6K is a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways[3]
Activated S6K was shown to be involved in endocrine resistance[4], as well as CDK4/6 inhibitor resistance[5]
Rupitasertib (formerly DIACC3010)[6] targets S6K to provide potent PAM pathway inhibition, while simultaneously targeting AKT 1/3 to overcome the compensatory feedback loop[7] (sparing AKT2 to limit the impact on glucose metabolism)

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.
In combination with endocrine therapy, phase 1 data show longer mPFS in patients with ESR1 mutations (AACR poster 2023)
Synergistic efficacy with rupitasertib in combination with a SERD was further demonstrated in ESR1 mutant ER+ HER2- breast cancer model (undisclosed)

Poster presented at AACR2023

Clinical Development

Clinical (phase 1) and preclinical (xenograft models) data supports the clinical development of rupitasertib in combination with a SERD, in ESR1 mutant ER+ HER2- metastatic or advanced breast cancer, in a Phase 1b trial which is expected to start in 2026.

References

1 Tsimberidou et al. Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer. J Hematol Oncol 2021, 14: 127

2. Wu et al. Beyond controlling cell size: functional analyses of S6K in tumorigenesis. Cell Death Dis. 2022; 13:646

3. Romano et al. A preexisting rare PIK3CA^E545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling, Cancer Discov 2018, 8:556
4. Artemenko et al. p70 S6 kinase as a therapeutic target in cancers: More than just an mTOR effector. Cancer Letters 2022, 535:215593
5. Mo et al. S6K1 amplification confers innate resistance to CDK4/6 inhibitors through activating c Myc pathway in patients with estrogen receptor positive breast cancer, Cancer 2022, 21:171
6. DeSelm et al. Identification of clinical candidate M2698, a dual p70S6K and Akt inhibitor, for treatment of PAM pathway-altered cancers, J Med Chem 2021, 64:14603
7. O’Reilly et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt, Cancer Res 2006, 66:2500