CDK4/6 Inhibitors in Pancreatobiliary Cancers: Opportunities and Challenges

Abstract

Existing treatment strategies for pancreatobiliary malignancies are limited. Nowadays, surgery is the only path to cure these types of cancer, but only a small number of patients present with resectable tumors at the time of diagnosis. The notoriously poor prognosis, lack of diverse treatment options associated with pancreaticobiliary cancers, and their resistance to current therapies reflect the urge for the development of novel therapeutic targets. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as an attractive therapeutic strategy in a number of cancers since their approval for treatment in patients with ER+/HER- breast cancer in combination with antiestrogens. In this article, we discuss the therapeutic potential of CDK4/6 inhibitors in pancreatobiliary cancers, notably cholangiocarcinoma and pancreatic ductal adenocarcinoma.

Keywords: CDK4/6 inhibitors; cholangiocarcinoma; pancreatic ductal adenocarcinoma.

Figure 1

RB pathway and G1/S cell cycle control. Cyclin (CCN); Cyclin-dependent kinase (CDK); Retinoblastoma protein (RB); E2F transcription factor (E2F).

Figure 2

Chemical structures of CDK4/6 inhibitors (source: selleckchem.com (accessed on 16 January 2023)).

Figure 3

Most frequent genomic alterations in eCCA and iCCA, (*) genes with the highest alteration frequency [59] extracted from (http://cbioportal.org (accessed on 16 January 2023)) [70,71].

Figure 4

OncoPrint of the RB pathway alterations in CCA, showing mutations and copy number alterations (The Cancer Genome Atlas Program (TCGA)).

Figure 5

Oncoprint of the RB pathway genomic alterations in PDAC, showing mutations and copy number alterations (TCGA).

Figure 6

CDKN2A gene alterations in human cancers (TCGA pancancer data).

Figure 7

Proportion of tumors with an elevated CDKN2A level (TCGA database). The tumor types analyzed in the TCGA study are indicated in the first column. The numbers of tumors of each study with a low or normal CDKN2A expression is indicated in the second column. The numbers of tumors with elevated CDKN2A expression (comparable to the expression reached in HPV+ tumors) are indicated in the third column. The proportion with respect to the total of tumors with elevated CDKN2A is indicated in the forth column ("Percent") for each study. Tumors of the pancreas or cholangiocarcinoma are highlighted in green. The color code on the right indicates whether a predictive test would be needed to select responsive patients. In red, a test is unlikely to be useful because almost 90% of the tumors have elevated CDKN2A and likely lacks phosphorylated CDK4. CDK4 inhibitors should not be considered to treat patients with this type of tumor. In green, a test is absolutely required to identify potentially responsive patients. In grey, a test may be required to identify unresponsive patients after an eventual stratification by molecular subtypes. In orange, a test is probably not useful as less than 5% of the tumors have elevated CDKN2A likely associated with absent phosphorylation of CDK4. The use of CDK4 inhibitors to treat these tumors is worthwhile to consider as most of them will be sensitive to the drug, at least initially.