The Therapeutic Potential of CRISPR/Cas9 Systems in Oncogene-Addicted Cancer Types: Virally Driven Cancers as a Model System

Abstract

The field of gene editing is undergoing unprecedented growth. The first ex vivo human clinical trial in China started in 2016, more than 1000 US patents have been filed, and there is exponential growth in publications. The ability to edit genes with high fidelity is promising for the development of new treatments for a range of diseases, particularly inherited conditions, infectious diseases, and cancers. For cancer, a major issue is the identification of driver mutations and oncogenes to target for therapeutic effect, and this requires the development of robust models with which to prove their efficacy. The challenge is that there is rarely a single critical gene. However, virally driven cancers, in which cells are addicted to the expression of a single viral oncogene in some cases, may serve as model systems for CRISPR/Cas therapies, as they did for RNAi. These models and systems offer an excellent opportunity to test both preclinical models and clinical conditions to examine the effectiveness of gene editing, and here we review the options and offer a way forward.

Prognostic and clinicopathological significance of CTTN/cortactin alterations in head and neck squamous cell carcinoma: Systematic review and meta‐analysis

“…The option of targeting cortactin derives from observations in cell lines and animal experiments, but further research is needed to design molecules that selectively inhibit cortactin . Other targeting strategies could be based on elimination of the amplified CTTN gene by means of CRISPR/Cas9 genome‐editing technology, or by the independent or cooperative repression of the CTTN , CCND1, and FADD oncogenes harbored by the 11q13 amplicon via epigallocatechin‐3 gallate . Other proposed approaches include the administration of anti‐EGFR drugs such as cetuximab and/or gefitinib, given the involvement of EGFR in certain pathways that oncogenetically activate cortactín (EGFR‐Src), and the possible co‐amplification of their respective chromosomic bands, 7p11 and 11q13, with co‐expression of their products .…”

“…11 Other targeting strategies could be based on elimination of the amplified CTTN gene by means of CRISPR/Cas9 genomeediting technology, 70,71 or by the independent or cooperative repression of the CTTN, CCND1, and FADD oncogenes harbored by the 11q13 amplicon via epigallocatechin-3 gallate. 11,12,67,72,73 Other proposed approaches include the administration of anti-EGFR drugs such as cetuximab and/or gefitinib, given the involvement of EGFR in certain pathways that oncogenetically activate cortactín (EGFR-Src), 11 and the possible co-amplification of their respective chromosomic bands, 7p11 and 11q13, 74 with co-expression of their products. 47 In addition, the reported involvement of cortactin in acquired resistance to gefitinib-based treatments suggest a potential role for the combination of this anti-EGFR monoclonal antibody with future cortactin-inhibiting molecules.…”

An update of knowledge on cortactin as a metastatic driver and potential therapeutic target in oral squamous cell carcinoma

“…One therapeutic approach would be to target genes amplified in chromosome band 11q13. The following strategies have been proposed: (a) Elimination of amplified CTTN gene by CRISPR /Cas9 genome edition technology (Doudna & Charpentier, ; Jubair & McMillan, ); (b) the independent or cooperative repression of oncogenes harbored by amplicon 11q13 ( CTTN , CCND 1, and FADD ) using epigallocatechin‐3 gallate (Alway et al., ; Hwang et al., ; Ramos‐García, Gil‐Montoya, et al., ); (c) the development and utilization of selective cortactin inhibitor molecules, given the high incidence of cortactin overexpression in HNSCC and OSCC ; (d) the administration of anti‐ EGFR drugs (e.g., cetuximab or gefitinib), based on reports of EGFR involvement in pathways that oncogenically activate cortactin ( EGFR ‐Src), and of drugs aimed at co‐amplification of their respective chromosome bands (7p11 and 11q13) (Garnis et al., ), with co‐expression of their products (Hofman et al., ); in fact, combined therapy with gefitinib and future cortactin inhibitory molecules (b+c) may be relevant, given the known involvement of cortactin in acquired HNSCC treatment resistance (Timpson et al., ), while a further option would be to target pathways that regulate oncogenic cortactin functions; (e) the utilization of saracatinib, which selectively inhibits Src activity and appears to reduce Src activation and inhibit that of its substrates downstream, blocking cortactin phosphorylation in Tyr421 (Ammer et al., ); saracatinib has been found to act dose‐dependently and reduce cortactin expression levels at high doses (0.5–1 μM) (Ammer et al., ); (f) the utilization of SU 6656, another Src‐selective inhibitor, which also suppresses the invadopodial function in HNSCC , likely by blocking the EGFR ‐Src‐cortactin‐invadopodia pathway (Hayes et al., ); and (g) administration of inhibitors of the MAPK pathway, for example, PD 98059, to block members of this pathway that interact with cortactin, for example, MEK and Erk (Campbell et al., ; van Damme et al., ; Hayes et al., )…”

“…This concept is especially relevant in relation to CTTN /cortactin in OSCC, because inactivation of an isolated oncoprotein can suffice to block the proliferation and survival of cancer cells, despite multiple summative oncogenic events. Hence, the utilization of CRISPR/Cas9 technology against certain oncogenes (e.g., CTTN ) shows considerable promise (Jubair & McMillan, ). However, it has not been elucidated whether this influence results from individual actions of these oncogenes or from their cooperative effects.…”

“Duel” and “Duet”: The Paradox of Carcinogenic Viruses and Targeted Virotherapeutics

“…Carcinogenic viruses are inherently oncogene-addicted [43], by which tumorigenesis stems from expression of one or more episomes towards dysregulation of the host cell cycle. Because viral oncogenes are mostly well-characterized and transform healthy cells through an episomal method of inheritance, they are prime candidates for new gene-editing approaches to immunotherapeutics, which seek to prevent oncogene addiction from its onset by disrupting the process of episomal inheritance.…”