Therapeutic Landscape of Malignant Pleural Mesothelioma: Collateral Vulnerabilities and Evolutionary Dependencies in the Spotlight

Abstract

Malignant pleural mesothelioma (MPM) is the epitome of a recalcitrant cancer driven by pharmacologically intractable tumor suppressor proteins. A significant but largely unmet challenge in the field is the translation of genetic information on alterations in tumor suppressor genes (TSGs) into effective cancer-specific therapies. The notion that abnormal tumor genome subverts physiological cellular processes, which creates collateral vulnerabilities contextually related to specific genetic alterations, offers a promising strategy to target TSG-driven MPM. Moreover, emerging evidence has increasingly appreciated the therapeutic potential of genetic and pharmacological dependencies acquired en route to cancer development and drug resistance. Here, we review the most recent progress on vulnerabilities co-selected by functional loss of major TSGs and dependencies evolving out of cancer development and resistance to cisplatin based chemotherapy, the only first-line regimen approved by the US Food and Drug Administration (FDA). Finally, we highlight CRISPR-based functional genomics that has emerged as a powerful platform for cancer drug discovery in MPM. The repertoire of MPM-specific "Achilles heel" rises on the horizon, which holds the promise to elucidate therapeutic landscape and may promote precision oncology for MPM.

Keywords: CRISPR/Cas9; collateral and evolutionary vulnerabilities; malignant pleural mesothelioma; targeted therapy; tumor suppressors.

FIGURE 1

Genomic landscape of CDKN2A, BAP1, and NF2 in MPM. (A) Somatic mutations of CDKN2A, BAP1, and NF2 in The Cancer Genome Atlas (TCGA) samples of MPM patients (n = 87). Data were downloaded from cBioPortal. (B) Schemtatic illustrating the pathways mediated by the tumor suppressor proteins.

FIGURE 2

The concept of synthetic lethal vulnerabilities and cancer-specific dependencies. (A) Cancer cells with functional loss of a tumor suppressor (gene “A”) are contextually sensitive to inhibition of another gene product (gene “B”). (B) Cancer-specific dependencies co-opted by tumorigenesis are compelling therapeutic targets.

FIGURE 3

Therapeutic landscape of MPM. An overview of collateral vulnerabilities and evolutionary dependencies identified in therapy-naïve and chemo-resistant MPM.

FIGURE 4

CRISPR/Cas9 screening for cancer drug discovery in MPM. A schematic diagram of CRISPR/Cas9 screening using pooled sgRNA libraries. Depending on the experimental setting, comparison of sgRNA abundance with reference samples can identify essential genes for drug resistance, cell proliferation or context-dependent events (e.g., synthetic lethal vulnerability with specific mutations).