(PA-326) Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation in Multiple Myeloma

Oncogenic mutations in KRAS and NRAS are prevalent in relapsed and refractory multiple myeloma (MM).  Given the difficulties in directly targeting RAS, compounded by the heterogeneous genetic landscape and diverse RAS mutations in hematological malignancies, alternative therapeutic strategies are critically needed.  Therefore, we conducted multi-omic screening to identify novel regulators of RAS protein stability, aiming to uncover alternative RAS-targeting approaches relevant to these cancers.


Methods: We used a CRISPR screening approach to identify regulators of KRAS protein stability.

Results:

These screens revealed that PP1C dephosphorylates the conserved T148 residue on both KRAS and NRAS, a critical step that facilitates their proteasomal degradation via LZTR1.  Interestingly, PP1C and LZTR1 appear to preferentially regulate RAS stability in hematological cancers.  Furthermore, mutations at KRAS A146, a residue adjacent to T148 and frequently found in MM, led to resistance against LZTR1-mediated ubiquitination and degradation of RAS.  Our research also uncovered that PAK1 and PAK2 kinases counteract PP1C by phosphorylating T148, effectively protecting RAS from degradation.  Consequently, inhibiting PAK1/2 resulted in a reduction in RAS protein expression.


Conclusions:

These findings reveal a novel regulatory circuit controlling RAS stability.  This discovery offers a promising therapeutic strategy for targeting RAS-driven hematological malignancies.