5. Challenges and opportunities of targeting GPCRs in
cancer
Targeting GPCRs including those harboring mutations in cancer therapy
presents a dual landscape of challenges and opportunities. One
significant challenge lies in the diversity of GPCRs and their intricate
signaling networks including crosstalk with various cellular processes.
This will bring potential off-target effects and unintended consequences
on normal physiological functions, which make it complex to develop
broad-spectrum therapeutic interventions. Furthermore, identification of
cancer specific GPCR mutations while distinguishing them from natural
variants is another hurdle, requiring advanced genomic and
bioinformatics analyses. One of the primary challenges in this field is
the limited availability and accessibility of comprehensive datasets.
GPCR research suffers from relatively small and scattered datasets,
which can impede the identification of robust associations between GPCR
mutations and cancer. For example, when comparing the mutational
landscape of GPCRs with the mutations in kinases, GPCRs mostly have
widespread mutations with few identified clustering, while kinases
feature distinct mutational hotspots (Dixit et al. , 2009). The
absence of clearly defined structural hotspot mutations in GPCRs imply
that targeting GPCRs in cancer is more challenging compared to the
well-studied approach targeting kinases.
However, promising opportunities are present in cancer drug development
targeting GPCRs, especially those overexpressed in cancer cells (R. T.
Dorsam & J. S. Gutkind, 2007) and those involved in anti-cancer
immunomodulation (Qiu, Yu, & Ma, 2024). In recent years, antibodies
have shown the potential to revolutionize GPCR-targeted therapies with
their high specificity and affinity. Modified antibodies directed
against specific GPCRs can serve as precision tools, enabling treatment
with reduced off-target effects. For example, the first-in-class CCR4
antibody drug named Mogamulizumab has been approved for treatment of
T-cell leukemia-lymphoma with enhanced antibody-dependent cell-mediated
cytotoxicity (ADCC) activity (Beck & Reichert, 2012). Additionally,
novel allosteric modulators present a unique opportunity in
GPCR-targeted cancer therapy. By modulating GPCR activity via
non-competitive binding sites, allosteric modulators allow for a more
nuanced regulation of signaling pathways. This fine-tuned control can
offer advantages in specificity and selectivity, potentially avoiding
side effects associated with orthosteric ligands (Bartfai & Wang,
2013).
Another opportunity lies in the usage of unbiased “GPCRome” datasets.
The concept of the GPCRome refers to the comprehensive exploration of
GPCR gene expression, copy number variation, mutational signatures and
functions, offering a system level understanding of their roles in
cancer biology (Wu et al. , 2019). Leveraging the GPCRome could
facilitate the discovery of novel biomarkers for early diagnose of
cancer, and also accelerate drug discovery by identifying previously
overlooked GPCRs as potential therapeutic targets, highlighting their
signaling network, and uncovering their interactions within the tumor
microenvironment. For example, Arora et al . performed a
comprehensive analysis of extracellular GPCR networks in cancer
transcriptomic datasets, and found that many ligand-receptor axes,
including muscarinic, adenosine, 5-hydroxytryptamine and chemokine
receptors, are associated with patient survival and can be exploited to
inhibit cancer cell growth (C. Arora et al. , 2024). Furthermore,
the advent of single-cell GPCRomics has allowed researchers to unravel
the heterogeneity within cancer cell populations (P. A. Insel et
al. , 2019), and AI-driven structural biological studies have enhanced
our ability to understand the complexity of GPCR signaling networks
(Matic, Miglionico, Tatsumi, Inoue, & Raimondi, 2023). Besides,
experimental tools such as the PRESTO-Tango assay facilitates systematic
interrogation of GPCR signaling by coupling receptor activation to a
reporter system, uncovering novel druggable targets (Kroeze et
al. , 2015). Alternative methods such as DNA-encoded library (DEL)
screening and CRISPR-based profiling offer high-throughput platforms to
identify GPCR ligands and evaluate the functional consequences of
genetic alterations (Cai, El Daibani, Bai, Che, & Krusemark, 2023;
Kapolka et al. , 2020). Lastly, quantitative mass spectrometry in
combination with proximity labeling techniques such as BioID or APEX
enables precise mapping of context-dependent GPCR signaling networks and
post-translational modifications (Paek et al. , 2017). These
advancements of in silico and experimental techniques will
together make GPCR targeting in cancer a promising field.