# Common Genetically Altered Pathways as Targets for Therapy in Pancreatic Cancer

> **NIH NIH R01** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $392,993

## Abstract

Pancreatic ductal adenocarcinoma (PDA) has an exceedingly poor prognosis with a 5-year survival of only ~6%. Unlike many other cancers, current strategies do NOT target genetic features of PDA. In part, this is because PDA is viewed as a disease that is dominated by KRAS as the oncogenic driver. As a result, therapies delivered to PDA are not targeted based on biomarkers, and chemotherapy is the mainstay for treatment. To define new means to treat PDA, we performed genetic analysis of >100 PDA cases by exome sequencing. These data revealed aberrations in multiple pathways. In particular, alterations in chromosome stability processes or cell cycle control were observed in >75% of cases.  These pathways are inter-related, and would be expected to remain actionable in spite of the common
deregulated KRAS signaling in PDA.
Genetic alterations can lead to tumor-specific vulnerabilities that can be exploited for treatment. Here
we will approach rational targeting of genetic events in PDA using two complementary efforts. First, we have
defined loss/mutation of multiple pathways associated with chromosome-fidelity. These events individually are
rare, but when coalesced into pathways/functional groups represent >30% of PDA patents. Our group and
others have found that a specific subset of genetic events represent vulnerabilities that can be selectively
targeted. Most notably germline BRCA/PALB2 mutations are the basis of the only active Phase III trial for
patients with PDA. However, whether other pathways associated with chromosomal instability can be
effectively targeted is unknown. These findings provide the impetus for a detailed analysis of the confluence of
loss of genes involved in genome stability, resultant biological output in PDA, and selective therapeutic
sensitivities. Second, therapeutic strategies can re-instate tumor suppressor activities that have been
disrupted in PDA and limit proliferation to control disease. Loss of cell cycle regulatory control over CDK4/6
occurs frequently in >50% of PDA cases through loss of p16ink4a. Therefore, CDK4/6 inhibition would be
expected to be exceedingly effective in PDA treatment. However, the response to CDK4/6 inhibitors is variable
and cell cycle regulatory networks in PDA are particularly complex suggesting that other genetic events
impinge on the efficacy of CDK4/6 inhibition. These findings provide the basis for defining the determinants of
durable response to CDK4/6 inhibitors, delineating successful combination therapies, and defining the utility of
such agents in disease relevant models of PDA. In total, these studies interrogate the hypothesis that
therapeutic approaches targeting genetic features of PDA controlling genome stability and cell cycle
control will provide critical advances to treatment.

## Key facts

- **NIH application ID:** 9867678
- **Project number:** 5R01CA211878-04
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Erik Knudsen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,993
- **Award type:** 5
- **Project period:** 2017-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867678

## Citation

> US National Institutes of Health, RePORTER application 9867678, Common Genetically Altered Pathways as Targets for Therapy in Pancreatic Cancer (5R01CA211878-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9867678. Licensed CC0.

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