ALK/PIK3CA Genetic Coupling: Implications for Progression and Personalized Therapy in Head and Neck Cancer

Abstract:

Identification of “druggable” genetic events in human cancers has successfully accelerated personalized therapy development, leading to remarkable clinical responses in many advanced stage cancer patients. Genomic characterization of head and neck cancer (HNC) reveals a scarcity of immediate druggable (i.e. treatable with drugs) genetic events in the majority of patients. We have conducted a systematic druggable genome search on the whole-exome sequencing data from

302 US-HNC (TCGA) patient tumors. We identified a noticeable subset of HNC Qatients with

anaglastic lymyhoma kinase (ALK) gene aberrations (ALK mutations, gene amplification), which can potentially be targeted by 2 immediately available and clinically safe ALK inhibitors,

Crizotinib and Ceritinib. Our preliminary data from HNC cell line models indicate that tumor cells with endogenous Qoint mutation of the ALK gene are sensitive to both Crizotinib and Ceritinib. lmportantly, a very recent case report (May, 2015) showed that an Asian HNC patient, whose tumor harbored ALK-gene fusion, was responsive to Crizotinib treatment. These cumulative evidences strongly indicate HNC with various ALK aberrations can be responsive to ALK inhibitors, with potential clinical benefits.

Strikingly, in-depth clinical data analysis on US HNC samples reveals that among all identifiable HNC cases, ALK genomic aberrations are flly found in advanced (Stage 3 and 42 HN C Qatients, implicating a crucial role of ALK and/ALK-associated genomic events in HNC progression/aggressiveness. Subsequent genomic analysis revealed that as high as 70% of ALK-altered HNC tumors co-harbored high levels of amplification of another oncogene, PIK3 CA (Odd Ratio:l0.522, P:0.0007***), revealing a selective coupling of ALK aberrations and PIK3CA amplification in HNC progression. As both ALK and PIK3 CA are known drivers for oncogenesis,

we hypothesize that ALK and PIK3 CA genetic events “co-drive” HN C formation and aggressiveness, via an undefined mechanism, and targeting of ALK and/or PIK3 CA signaling

may be effective for advanced HNC. Here, we propose to:l) compare the ALK and PIK3CA genomic profiles (mutation, fusion, and gene copy number alterations) in Asian and US-HNC

patient tumors to define their clinical relevance in 2 major HNC populations; 2) determine to mechanistic involvement of ALK/PIK3CA coupling (vs. ALK alterations alone) in HNC tumorigenesis and invasion; and 3) to systematically examine the therapeutic efficacies of ALK and/PIK3CA inhibitors in relevant HNC models. The study not only defines the roles of emerging ALK alterations in HNC, in-depth mechanistic investigations of this novel “ALK/PIK3 CA genetic coupling” will have broad biologic, therapeutic (and likely diagnostic) implications for personalized theragy for advanced HNC.