Lung cancer cell response to Cdk4/6 inhibition
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Lung cancer is the most common cancer worldwide, accounting for over 1.8 million new cases per year and more than 1.6 million deaths. Smoking contributes to ~85% of lung cancer deaths and ~30% of all cancer deaths. In the United States, close to 160,000 patients are expected to die from lung cancer this year, which represents more than a quarter of all cancer deaths. Surgery, radiation, chemotherapy, targeted therapies, and immunotherapies—alone or in combination—are already used in the clinic to treat lung adenocarcinoma, with some success. However, there is still a huge need to develop more effective therapies. For example, some chemotherapies are only effective in small populations of lung cancer patients; others are successful in the short term but become ineffective over time because cancer cells develop resistance. We are researching a particular class of chemotherapy, with the goal of understanding how it can be improved to reach more patients and with more robust long-term outcomes.
 
 
 At its heart, cancer is a disease of too much cell proliferation. Normal cells have checkpoint mechanisms in place to only divide when and where absolutely required; in contrast, cancer cells undergo unchecked proliferation. A central regulator of proliferation is the so-called Rb pathway: this pathway is named after a protein (retinoblastoma or Rb), which acts as a cell cycle brake. In lung adenocarcinoma cells, the Rb cell cycle brake is often disabled through the hyperactivation of its regulators, the Cdk4 and Cdk6 proteins (Cdk4/6). Fortunately, inhibitors of Cdk4/6 have recently been developed and approved in the clinic to treat patients. One of these inhibitors, called palbociclib, was initially tested successfully in breast cancer patients and is now being tested in lung cancer patients. When palbociclib or similar drugs are given to patients, Cdk4/6 are inhibited in lung cancer cells, which means they cannot disable Rb. As a result, the brake is turned back on to stop or slow cell proliferation. Here, we propose to investigate the fundamental mechanisms that normally regulate the activity of Cdk4/6 and its response to palbociclib in lung cancer cells. We hope that by gaining a better understanding of these mechanisms, we will be able to enhance the effects of Cdk4/6 inhibitors and other drugs in patients with lung cancer. Our goal is to inform development of improved inhibitors that can be more broadly administered and have more robust long-term outcomes in patients. 
 
 
 We have two main goals: our first goal is to determine how another cell cycle protein, named p27, affects how Cdk4/6 is inhibited by palbociclib or other Cdk4/6 drugs. Our hypothesis is that binding of p27 to Cdk4/6 makes it insensitive to palbociclib. We are testing this idea using a combination of X-ray crystallography, which allows the visualization of protein structures, and experiments in cells. If our idea is correct, the amount of p27 in a lung cancer cell and p27 binding to Cdk4/6 may serve as markers for resistance to Cdk4/6 inhibitors. Our second goal is to identify new regulators of Cdk4/6 activity. To this end, we have already performed an experiment in which we tested the consequence of deleting each gene in the genome for how cells respond to palbociclib. By deleting genes one by one, we have found many new genes whose loss blocks or enhances the cell division arrest induced by treatment with palbociclib. We will use a number of molecular and cellular assays to determine how these regulators of Cdk4/6 activity function in lung cancer cells. These genes may become novel targets for therapy, in conjunction with Cdk4/6 inhibitors of other lung cancer drugs.