RAC1 Genomic Alterations Drive Head and Neck Cancer Progression

Abstract:

Identifying recurrent cancer gene mutations with exquisite drug sensitivity can directly impact patient treatment. Emerging evidences reveal a new class of mutations, called “neomorphic mutations” (or neomorphs: defined as gain-of-fiinction mutations with acquired new gene functions), which can be effectively exploited for therapeutic targeting in cancer often in a mutant-specific manner. Head and neck cancer (HNC) has a scarcity of immediately druggable genetic events, thus hampering precision medicine development. Here, we identify the first neomorphic mutation in HNC, namely RACI p.Al59V as a hotspot, druggable mutation in HNC. Clinical findings reveal that this RACI p.Al59V mutation alone is significantly associated with poor overall and disease-free survivals in HNC patients(US-TCGA). Our preliminary data demonstrates its robust driver activity for HNC cell proliferation, and it promotes HNC hyper-proliferation in “detached state” (a pre-requisite for cancer metastasis). Strikingly, RACI p.A1 59V acquires an unexgected “hygeractivated state of PI3K/AK T signaling” in HNC cells with exquisite sensitivity [or PI3K inhibitors. Subsequent COSMIC database analysis identifies RACI p.Al59V in an Asian recurrent HNC, consistent with the aggressive nature of this neomorph. RACI p.A1 5 9V also appears to have a potential female gender association among Caucasians. Furthermore, integrative genomic-proteomic analysis reveal that additional RACI mutations may also exploit/activate PI3K pathway in HNC. In fact, the only available RACI-mutated HNC cell line, HSC-3 of Asian origin, also harbors a PIK3 CA genomic event, supporting a RACI—PI3K—ness in HNC.

Our preliminary results first demonstrate a novel mechanism of PI3K/AKT hygeractivation driven by RACI Q.AI59V mutation in HNC. Our clinical and preclinical findings led us to hggothesize that RACI genomic aberrations are direct drivers [or HNC tumorigenesis, and activating RACI mutation(sg can induce a state PI3K/AKT hygeractivation via undefined

mechanism s in HNC cells which ma con er sensitivi to PI3K athwa inhibition. Here, we propose to: l)compare the RACI genomic profiles (both mutation and gene copy changes) in Asian and US-HNC patient tumors to define their clinical relevance in 2 major HNC populations, for its mutational profile, prognostic activity, and potential gender bias; 2)deterrnine the biological contributions of all HNC-associated RACI mutations and amplification to HNC growth, invasion, anoikis-resistance, tumor-forrnation; and 3)eXamine the PI3K-inhibitor sensitivity and elucidate the mechanism(s) of PI3K/AKT hyperactivation driven by RACI p.A1 59V, and possibly other HNC-associated RACI mutations in HNC systems. This translation study provides a genetic basis for precision treatment for a sizeable subset of HNC patients with clinically aggressive diseases for potential PI3K targeting (potentially benefiting ≫16 200 HNC patients/year).