KRAS signaling in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) arises from mesothelial cells lining the pleural cavity of asbestos-exposed individuals and rapidly leads to death. MPM harbors loss-of-function mutations in BAP1, NF2, CDKN2A, and TP53, but isolated deletion of these genes alone in mice does not cause MPM and mouse models of the disease are sparse. Here, we show that a proportion of human MPM harbor point mutations, copy number alterations, and overexpression of KRAS with or without TP53 changes. These are likely pathogenic, since ectopic expression of mutant KRAS G12D in the pleural mesothelium of conditional mice causes epithelioid MPM and cooperates with TP53 deletion to drive a more aggressive disease form with biphasic features and pleural effusions. Murine MPM cell lines derived from these tumors carry the initiating KRAS G12D lesions, secondary Bap1 alterations, and human MPM-like gene expression profiles. Moreover, they are transplantable and actionable by KRAS inhibition. Our results indicate that KRAS alterations alone or in accomplice with TP53 alterations likely play an important and underestimated role in a proportion of patients with MPM, which warrants further exploration.

KRAS Pathway Alterations in Malignant Pleural Mesothelioma: An Underestimated Player

“…In a recently published study by our group, we employed digital droplet PCR (ddPCR) to detect KRAS mutations in human MPM in comparison with lung adenocarcinoma samples with a high sensitivity (down to 1:20,000 mutant copies) [ 18 ]. In a significant proportion of human MPM samples (25%, 3/12), we were able to detect KRAS mutations, despite low copy numbers.…”

“…Additionally, we were also able to report that targeting oncogenic KRAS G12D to the murine pleura causes MPM, and in combination with TP53 loss elicits aggressive MPM with pleural effusions, secondary BAP1 mutations, and a transcriptome that resembles that of human MPM. Furthermore, these murine MPM were not only transplantable, but also actionable by KRAS inhibition using the phosphodiesterase δ blocker deltarasin, which inhibits membrane binding and hence activation of KRAS [ 18 ]. This study shows that, indeed, molecular alterations of KRAS and its downstream effectors might be more frequent and important than we currently think.…”

“…On the other hand, we recently discovered a cardinal role for KRAS signaling in MPM. In this article we identified low allelic frequency KRAS mutations by sensitive digital droplet polymerase chain reaction (PCR) in 25% of our MPM patients from Germany, copy number alterations in up to half of primary MPM cell lines from France, and found that ectopic KRAS G12D overexpression with or without Trp53 deletion in the pleural and peritoneal mesothelium of mice led to disease identical to human MPM [ 18 ].…”

“…Based on the above findings and a functional report of the interconnectedness of the KRAS and TP53 pathways [ 22 ], we hypothesize that KRAS pathway alterations might represent a widely underestimated player in MPM. In addition to our original research report, analyzing KRAS and TP53 mutations in human and experimental MPM [ 18 ], here we examine the whole KRAS pathway as proposed elsewhere [ 22 ] (indicated in Figure 1 a and including the following genes: KRAS, EGFR, NF2, BRAF, MAP2K1, MAPK1, PIK3CA, AKT1, RASSF1, STK3, LATS1, MDM2, TP53 ). For this, the relevant literature is reviewed, and publicly available datasets are analyzed as follows.…”

An In Vivo Inflammatory Loop Potentiates KRAS Blockade

“…Our results suggest that canakinumab might be selectively effective against KRAS-mutant cancers and warrant an a posteriori analysis of CANTOS results with respect to KRAS mutation status. In addition, the inflammatory loop described herein needs to be tested and validated in a new molecular subtype of malignant pleural mesothelioma we recently discovered [51].…”