NOVEL INSIGHTS IN ADVANCED THYROID CARCINOMA: FROM MECHANISMS TO TREATMENTS: Molecular insights into the origin, biology, and treatment of anaplastic thyroid carcinoma

Abstract

Anaplastic thyroid carcinoma (ATC) is among the most daunting entities in clinical oncology. Large-scale genomic studies of thyroid cancer within the last decade have uncovered a distinct set of recurrent somatic alterations implicated in the development, aggressiveness, and treatment resistance of ATC. The sequence of events leading to the development of ATC commonly begins with a tumorigenic mutation that constitutively activates the mitogen-activated protein kinase (MAPK) pathway, giving rise to indolent entities such as well-differentiated papillary or follicular thyroid carcinomas. This is followed by recurring alterations that drive oncogenic properties such as enhanced proliferation, genomic instability, replicative immortality, and dedifferentiation, culminating in the emergence of highly aggressive ATC tumors. The truncal MAPK-activating events present therapeutic opportunities, as small molecule inhibitors against key components of this pathway are available. Indeed, genotype-guided targeting of the MAPK pathway is now the standard of care for subgroups of ATC patients, and further efforts exploring additional MAPK inhibitors and the combination of immune checkpoint blockade with MAPK inhibition are overcoming resistance to the current targeted therapies in the clinic and expanding our arsenal against this disease. In this review, we summarize the current understanding of the genomic landscape of ATC, discuss the biological and clinical ramifications of recurring aberrations, and provide an overview of the opportunities and challenges in the clinical management of this lethal malignancy.

Keywords: anaplastic thyroid carcinoma; genomics; immunotherapy; targeted therapy.

Figure 1

Moderate alteration burden and the stepwise evolution of ATC. (A) The comparison of the genomic alteration burden of tumors shows that, while ATC tumors exhibit higher alteration burdens compared to papillary thyroid cancer, they occupy a low-to-moderate position across the different cancer types (the lollipops solely show the increasing order of the alteration burdens of different cancer types and do not represent actual values). (B) A sequential acquisition of alterations drives the transformation of thyrocytes to ATC. This process is commonly initiated with an alteration constitutively activating the MAPK pathway, giving rise to premalignant or malignant entities with high levels of differentiation and indolent characteristics. This is followed by additional alterations that lead to further dedifferentiation of cells and the acquisition of aggressive traits. Consistent with this model, genomic features of well-differentiated thyroid tumors are also observed in the advanced tumors, reflecting their origin as a truncal event. In contrast, alterations driving the progression of the disease are rare and subclonal in well-differentiated tumors and become enriched in the advanced disease. Moreover, a co-occurring differentiated thyroid cancer (co-DTC) is frequently observed in ATC, consistent with a branching evolution during the development of the disease. The clonal separation of these two components can hypothetically occur at any stage of the disease progression. Representative high-power field images show ATC and co-DTC components of the same tumor. Genomic characterization of the co-occurring DTCs in the GATCI cohort indicated that co-DTC tracks with the advanced forms of thyroid cancer, and the common ancestor harbored ∼95% of CNAs and ∼20% of SNVs in the two components. The lengths of the lines in the depicted phylogenetic tree are hypothetical, as sufficient data to accurately estimate the average evolutionary distance of the different components is not available. The data and plots for this figure are adapted from (8). Mbp, megabase pair; PGA, percentage of genome altered; DDR, DNA damage response.

Figure 2

Key components of MAPK and PI3K/AKT pathways in ATC. The canonical MAPK pathway is initiated by the RTKs binding to their ligands. This binding induces dimerization and activation of the RTKs which, in turn, recruit the guanine nucleotide exchange factor (GEF) SOS and promote the exchange of GDP for GTP on RAS, thereby activating it. Subsequently, RAS induces the dimerization and activation of RAF proteins. This is followed by sequential phosphorylation and activation of MEK and ERK. ERK then mediates the downstream functions of the pathway by interacting with a multitude of effectors. ERK also participates in the negative regulation of MAPK signaling through direct interaction with the members of the pathway, as well as upregulation of negative regulators of MAPK signaling. PI3K is activated downstream of both RTKs and GPCRs. PI3K catalyzes the transfer of a phosphate group to phosphatidylinositol 4,5-bisphosphate (PIP2), converting it to phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 then induces the activation of AKT. Activation of AKT leads to derepression and activation of the mTOR complex 1 (mTORC1; presented as mTOR interacting with RAPTOR). AKT and mTORC1 are the primary nodes orchestrating the diverse functions of the PI3K/AKT pathway by interacting with numerous effectors. The rates of mutations in selected genes in ATC shown on the plots are derived from references (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20).

Figure 3

Response and resistance to first-generation RAF inhibitors. The first panel illustrates MAPK signaling in BRAF^V600E-mutant cells. In these cells, monomeric signaling by BRAF^V600E leads to continuous activation of ERK and suppression of dimeric signaling through the negative feedback by ERK. The second panel shows the inhibition of the upregulated MAPK output by first-generation RAF inhibitors. First-generation RAF inhibitors (represented by dabrafenib) selectively inhibit the monomeric signaling by BRAF^V600E, but they promote dimeric signaling by RAF through direct recruitment of RAF to RAS and stabilization of dimerization, as well as through relief of the feedback inhibition by ERK. These mechanisms might contribute to the development of adaptive resistance to first-generation RAF inhibitors. The third panel shows adaptive/acquired resistance to first-generation RAF inhibitors. Any mechanism that leads to dimeric signaling by RAF causes innate, adaptive, or acquired resistance to first-generation RAF inhibitors. These include RAS mutations, NF1 LOF, BRAF class II and III mutations (mutations other than alteration of the V600 that lead to either RAS-independent or RAS-dependent dimerization of RAF), and RTK fusions or upregulation.