RAC1 P29S

The presence of recurrent RAC1 mutations in undifferentiated melanoma is also notable as these alterations may contribute to mitogen-activated protein (MAP) kinase pathway targeted therapy resistance. Furthermore, the RAC1 alterations identified in this cohort have been shown to drive a melanocytic to mesenchymal switch in melanocytes, offering a possible explanation for the undifferentiated phenotype of these melanomas.

Our results unprecedentedly elucidate that P29Q/S-induced structural and dynamical perturbations of Rac1 core domain weaken the binding of the catalytic site Mg2+ ion, and reduce the GDP residence time within protein, enhancing the GDP/GTP exchange rate and Rac1 activity. This broadens our knowledge of the role of cancer-associated mutations on small GTPases mechanism supplying valuable information for future drug discovery efforts targeting specific Rac1 isoforms.

RAC1 mutated melanomas are rare, mostly of cutaneous origin and frequently harbour concomitant MAP kinase mutations, particularly in NRAS. Patients with advanced disease benefit from systemic treatment with ICI.

We also validated this finding by immunofluorescent staining of PD-L1 and M2 Macrophages in immunocompetent mouse HNSCC xenografts models expressing RAC1 p.P29S and p.A159V mutations as compared to controls.Our in silico, in vitro and in vivo findings first uncover an important role of RAC1 aberrations in HNSCC TIME immunosuppression by regulating PD-L1 expression, neutrophil and M2 macrophages infiltrations. Clinical activities of PD-L1 inhibitors in RAC1-mutated HNSCC patients worth future investigations.

Higher numbers of mutations were present in melanomas compared to their precursor naevi. These findings support the further evaluation of this melanoma custom NGS panel as an ancillary test for interpreting difficult borderline melanocytic lesions.

Thus, targeting RAC1 represents a promising strategy for cutaneous melanoma therapy, as well as for inhibition of other signaling activation that promotes resistance to targeted therapies. In this review, we focus on the role of RAC1 in metastatic cutaneous melanoma emphasizing the anti-metastatic potential of RAC1- targeting drugs.

On the other hand, in Rac1-GTP, some of the contacts of the guanosine ring of GTP with Rac1 are temporarily lost, enabling the guanosine ring to move toward Switch I and subsequently close the switch. Rac1-GTP adopts a Ras state 2 like conformation, where both switch regions are in closed conformation and Thr35 forms a hydrogen bond with the nucleotide.

RAC1 amplification and gain, which accounts for 39.5% of HNSCC are also significantly associated with poorer OS and DFS (P<0.01).While HNSCC is one of the most highly immune infiltrated cancer types with promising results in clinical trials of immune checkpoint inhibitors, e.g. nivolumab, we examined the potential involvement of immune-related events to the dismal outcomes of RAC1-mutated HNSCC patients...We also examined the mRNA expression of the immunomodulatory genes in RAC1-mutated vs. RAC1-wildtype HNSCC tumors. RAC1-mutated patients have significantly higher expression of pro-inflammatory CXCL9 and CXCL10 (p=0.01) as well as druggable targets CD274 (PD-L1) (p=0.014) and IL2 (p<0.01).Taken together, RAC1 mutations may contribute to an immunosuppressive tumor microenvironment in HNSCC, first highlighting potential immunological roles of RAC1 aberrations in HNSCC.

Time-lapse tracking of melanocytes in co-culture revealed dynamic interaction-phenotypes and hyper-motile cell states that indicated that, in addition to the known role in activating mitogenic signalling, MEK-pathway activating mutations may also allow melanocytes to escape keratinocyte control and increase their invasive potential. Expanding this combinatorial platform will identify other therapeutic target mutations and melanocyte genetic variants as well as increase understanding of skin cell interactions.