CDKN2B deletion is essential for pancreatic cancer development instead of unmeaningful co-deletion due to juxtaposition to CDKN2A

Abstract

Pancreatic cancer is among the deadliest malignancies; however, the genetic events that lead to pancreatic carcinogenesis in adults remain unclear. In vivo models in which these genetic alterations occur in adult animals may more accurately reflect the features of human cancer. In this study, we demonstrate that inactivation of Cdkn2b (p15ink4b) is necessary for induction of pancreatic cancer by oncogenic KRASG12D expression and inactivation of Tp53 and Cdkn2a in adult mouse pancreatic ductal cells (P60 or older). KRASG12D overexpression in these cells activated transforming growth factor-β signaling and expression of CDKN2B, which, along with CDKN2A, led to cellular senescence and protected cells from KRAS-mediated transformation via inhibition of retinoblastoma phosphorylation. These results show a critical role of CDKN2B inactivation in pancreatic carcinogenesis, and provide a useful adult animal model by genetic engineering via lentiviral delivery.

A functional variant rs1537373 in 9p21.3 region is associated with pancreatic cancer risk

“…In the induction of PC experiment in adult mice, only simultaneous inactivation of Cdkn2a and Cdkn2b could result in PC development at 4 weeks post‐injection. And Cdkn2b inactivation was necessary for Rb phosphorylation and to encompass cellular senescence …”

“…And Cdkn2b inactivation was necessary for Rb phosphorylation and to encompass cellular senescence. 49 To the best our knowledge, it is the first study comprehensively explored the associations between the variants in 9p21.3 and risk of PC in a Chinese population. Nevertheless several limitations of our study should be acknowledged.…”

WNT inhibition creates a BRCA-like state in Wnt-addicted cancer

“…Among the well-established markers of senescence, CDKN2A (encoding 16 INK4a and p14 ARF ) is inactive in HPAF-II cells due to a large in-frame deletion (COSMIC database). CDKN2B (encoding p15INK 4b ) acts as a tumor suppressor by promoting cell cycle arrest and senescence in the absence of 300 CDKN2A, especially in pancreatic cancer (51,52). The expression of CDKN2B was significantly enhanced in tumors from mice treated with ETC-159 alone and further increased in tumors treated with the combination containing olaparib ( Figure 6C).…”

Personalized Cancer Therapy Prioritization Based on Driver Alteration Co-occurrence Patterns

“…A total of 276 PDXs were treated in at least one of the 53 treatment groups considered, each treatment being tested in 29 to 246 animals, with a median of 43 (IQR: . We could obtain the molecular profile for 187 of them, which had been treated with a median of 18 (IQR: [14][15][16][17][18][19][20] drugs. The final dataset consisted on 3,127 experiments performed on 187 PDXs and 53 treatment responses, across 5 tumor types: BRCA (breast cancer, n=38), CM (cutaneous melanoma, n=32), COREAD (colorectal carcinoma, n=51), NSCLC (non-small cell lung carcinoma, n=27), PAAD (pancreatic adenocarcinoma, n=38), and 1 PDX without tumor type annotation).…”

“…However, most tumors do not present a single actionable mutation but have co-occurring driver alterations that might simultaneously alter key players of signaling pathways connected by cross-talk and feedback mechanisms [15,16]. There are many documented cases of functionally relevant co-occurring oncogenic mutations, such as the concomitant inactivation of TP53 and RB1 [17], co-deletion of CDKN2A and CDKN2B [18], co-amplification of MDM2 and CDK4 [19,20], 1p/19q co-deletion in glioma [21], MYC amplification and TP53 mutations [22] or activating alterations in KRAS and BRAF [5]. At pathway level, the concomitant activation PI3K signaling pathway with FGF signaling (FGFR2 and FGFR3), or with NRF2 mediated oxidative response have also been identified in several tumor types [16].…”