A CRISPR Path to Finding Vulnerabilities and Solving Drug Resistance: Targeting the Diverse Cancer Landscape and Its Ecosystem

Abstract

Cancer is the second leading cause of death globally, with therapeutic resistance being a major cause of treatment failure in the clinic. The dynamic signaling that occurs between tumor cells and the diverse cells of the surrounding tumor microenvironment actively promotes disease progression and therapeutic resistance. Improving the understanding of how tumors evolve following therapy and the molecular mechanisms underpinning de novo or acquired resistance is thus critical for the identification of new targets and for the subsequent development of more effective combination regimens. Simultaneously targeting multiple hallmark capabilities of cancer to circumvent adaptive or evasive resistance may lead to significantly improved treatment response in the clinic. Here, the latest applications of functional genomics tools, such as clustered regularly interspaced short palindromic repeats (CRISPR) editing, to characterize the dynamic cancer resistance mechanisms, from improving the understanding of resistance to classical chemotherapeutics, to deciphering unique mechanisms that regulate tumor responses to new targeted agents and immunotherapies, are discussed. Potential avenues of future research in combating therapeutic resistance, the contribution of tumor-stroma signaling in this setting, and how advanced functional genomics tools can help streamline the identification of key molecular determinants of drug response are explored.

Shedding light on the dark genome: Insights into the genetic, CRISPR-based, and pharmacological dependencies of human cancers and disease aggressiveness

“…Consequently, these results provide valuable insights into the genetic mechanisms involved in these cancers and suggest that these genes could serve as potential targets for the development of novel therapies. Therefore, the CRISPR-based gene editing technology used in the Achilles project has the potential to provide valuable insights for developing new cancer treatments and ultimately improving outcomes for cancer patients [ 33 , 49 – 57 ].…”

Preclinical Anticipation of On- and Off-Target Resistance Mechanisms to Anti-Cancer Drugs: A Systematic Review

“…Especially, pairing with functional genomics data such as single-cell sequencing and spatial transcriptomics provides hope for major advances [206][207][208][209][210]. There are now a growing number of examples where a CRISPR/Cas-based screen allowed to identify pathways responsible for de novo or acquired drug resistance pathways, including activation of alternative pathways, chromatin reprogramming, and cell lineage switches [126,129,130]. Recently, CRISPR screenings have been performed in patient samples to guide subsequent treatments, mostly in hematological tumors where tumor samples are more easily accessible, but subsequent clinical translation has proven difficult [211].…”

“…As mentioned above, CRISPR/Cas9 strategies are now frequently adopted for conducting comprehensive genetic screens in order to investigate gene function [17,59,85,[126][127][128][129][130][131][132]. In the widely used knockout procedure, the Cas9 nuclease and a sgRNA precisely directing Cas9 to the targeted location are delivered into the cell of interest.…”

Precision in Action: The Role of Clustered Regularly Interspaced Short Palindromic Repeats/Cas in Gene Therapies

“…It is vital to point out that CRISPR techniques enhance drug sensitivity. CRISPR edits genes involved in drug resistance pathways, which makes cancer cells more prone to traditional therapies [ 285 ]. A considerable example is the ability of CRISPR to enhance the effectiveness of chemotherapy drugs that are involved with leukemia treatment [ 285 ].…”