Targeting Cancer's Achilles Heel: DNA Damage Response Networks Beyond PARP

In 2015, 3 scientists were awarded the Nobel Prize in Chemistry for their work detailing the molecular mechanisms that cells use to repair damaged DNA.¹ Numerous repair pathways are activated in response to different types of damage, regulated and coordinated by the broader DNA damage response (DDR) network.

Defects in the DDR are a recognized hallmark of cancer, allowing oncogenic alterations in the genome to go unrepaired and fueling cancerous growth. But cancer cells must maintain a delicate balance to prevent catastrophic levels of DNA damage from triggering cell death, and their heavy reliance on the remaining normal DDR components creates a therapeutically targetable Achilles’ heel (Figure).^2-4

The proof of concept is the development of PARP inhibitors, which have demonstrated significant efficacy in the treatment of tumors with mutations in the BRCA1/2 genes that encode proteins involved in the repair of double-stranded DNA breaks (DSBs).

Three PARP inhibitors are approved for the treatment of ovarian cancer: olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula). Olaparib and rucaparib received regulatory approval for advanced ovarian cancer with BRCA1/2 mutations confirmed by a companion diagnostic. Olaparib is indicated for patients who have received at least 3 prior treatment regimens; rucaparib, for those who have received 2 or more. All 3 drugs are approved in the maintenance setting earlier in the course of disease in patients who experienced at least a partial response (PR) to chemotherapy, regardless of their BRCA1/2 mutation status.⁵

Olaparib was also recently approved for the treatment of BRCA1/2-mutant, HER2-negative metastatic breast cancers in patients who have previously received chemotherapy or, in the case of patients with hormone receptor—positive disease, endocrine therapy. Additionally, talazoparib (Talzenna) gained FDA approval for patients with germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer.

Although PARP inhibitors have undeniably proved paradigm changing for the treatment of certain cancers, the overwhelming majority of patients will ultimately develop resistance and disease recurrence via resistance mechanisms that include reversion to wild-type BRCA1/2 status.

Figure. Major DNA Repair Pathways and Potential Therapeutic Targets^2-4

Maintaining Genomic Integrity

As a result, the DDR network, which involves more than 450 proteins, is ripe for continued therapeutic exploitation. Improved understanding of its intricacies is helping advance this goal. They offer up a host of potential therapeutic targets beyond PARP that are now beginning to be explored (Table).Cells are constantly under attack from a wide variety of potentially DNA-damaging assailants both within the organism and in the surrounding environment. DNA can be damaged by, among other things, exposure to ultraviolet light, ionizing radiation, toxic chemicals, reactive oxygen species, mechanical stress, and replication errors.

In response, cells have developed a complex network of hundreds of proteins organized into molecular machines that detect damage and either repair it or—if the damage is catastrophic— trigger cell death. Known collectively as the DDR, this network is essential to maintaining the genomic integrity that is vital to the health of the organism.

The specific components of the DDR that are activated depend upon both the specific assault and the type of damage it inflicts, from a simple change in a single base pair to breaks in the DNA.

A diverse range of sensory proteins serve on the frontline, detecting the damaged DNA and setting in motion the DDR pathways that orchestrate the appropriate downstream cellular responses.

Downstream of these damage sensors, the central regulators of the DDR are 3 structurally unique serine/threonine kinases: ataxia telangiectasia mutated (ATM), ataxia telangiectasia and RAD3 related (ATR), and DNA-dependent protein kinase (DNA-PK). ATM and DNA-PK are activated predominantly in response to DSBs, whereas ATR is activated in response to single strand breaks (SSBs), although it does also play a backup role in the DSB response.

These kinases phosphorylate both themselves and a range of downstream targets, further amplifying the damage signal. Among the hundreds of downstream targets for ATM and ATR are key proteins involved in checkpoints at which the cell cycle can be paused to give the cell time to repair the DNA before it is used as a template to synthesize new DNA (G1/S transition checkpoint) or to repair any damage that occurs during DNA replication (S phase checkpoint) or before the cell irreversibly commits to entering mitosis (G2/M checkpoint).^6,7

Table. Therapeutic Targeting of the DNA Damage Response in Clinical Trials

DNA Repair Mechanisms

ATM and ATR activate the checkpoint kinases CHK2 and CHK1, respectively. Downstream of these kinases is another host of targets involved in cell-cycle arrest, DNA repair, and cell death. The determination of cell fate—arrest and repair versus death—is a highly dynamic process influenced by a delicate balance of the specific pathways activated and the relative levels of the different proteins.^2-4The DDR network regulates DNA repair directly through activation of the component proteins of DNA repair pathways and in 2 other, more subtle ways. First, it modifies the chromatin close to the site of the DNA damage, facilitating the recruitment of other DNA repair components. In addition, it acts on a more global level to regulate transcription, levels of deoxynucleotides, and more, creating an environment that is conducive to DNA repair.

There are 4 major types of DNA repair, some of which have multiple different sub-pathways and the type of DNA damage incurred regulates which of the DNA repair pathways is activated. When the damage is limited to just 1 strand of the DNA, an SSB, the other strand can be used as a template for repair. Nucleotide excision repair is the most flexible type of SSB repair, acting on various types of DNA damage; base excision repair (BER) is used to repair nonbulky damage to DNA bases, and mismatch repair (MMR) is used to repair errors that occur during DNA replication.

An Achilles Heel

The final type of DNA repair is DSB repair; these are the most toxic form of damage and their repair is accomplished through the homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. The former is carried out during the S and G2 phases of the cell cycle, when an undamaged sister chromatid is available to use as a template, and as such it is error-free. NHEJ repairs DSBs at any stage of the cell cycle since it does not require a homologous template. However, that also renders it more error prone than the HR pathway.^4,8-11DNA damage is now widely recognized as 1 of the hallmarks that enable the transformation of normal cells into malignant ones. Its important role in cancer is reinforced by the fact that inherited defects in DDR network components are associated with increased cancer predisposition. Oncogenic stresses, such as lack of nutrients and oxygen and continued exposure to carcinogens, foster a background of continual, ongoing DNA damage in cancer cells. Because of redundancies and cross-talk within the network, when 1 pathway is defective, its loss is compensated for by the activation of other pathways. The cancer cell faces a delicate balance between fostering genomic instability and maintaining a functional DDR to prevent the accumulation of toxic intermediates that trigger cell death. As a result, the defective DDR becomes a targetable Achilles’ heel.

The therapeutic exploitation of DNA damage was first pursued in the development of DNA-damaging chemotherapies, which include alkylating drugs, cross-linking agents, and therapies that induce DNA strand breaks. Advances in our understanding of the intricacies of the DDR network have been instrumental to the development of new drugs and have driven the idea of synthetic lethality, whereby pharmacologic suppression of DDR components enhances the efficacy of DNA-damaging chemotherapeutics and radiation therapy or combines with preexisting nonlethal DNA damage defects, tipping the cell over the edge and triggering apoptosis.

Taking Out the Big Three

This strategy was exploited in the development of PARP inhibitors, which block the PARP1 enzyme involved in SSB repair. The unrepaired SSBs can generate DSBs, which are repaired by the HR pathway that involves the BRCA1/2 proteins. Patients with defective BRCA1/2 genes are exquisitely sensitive to PARP inhibitors because those DSBs cannot be repaired, triggering cell death. Other defects within the HR pathway that can confer sensitivity to PARP inhibition are also beginning to be elucidated.^2-4Inhibitors of the 3 central kinases of the DDR are the most obvious potential targets for attacking repair mecahnisms, and, despite some challenges, several agents are in clinical development (Table). Celgene’s CC-115 is a dual inhibitor of DNA-PK and mammalian target of rapamycin (mTOR). Several trials are ongoing; the results of a phase I study in patients with advanced solid tumors and hematologic malignancies were published in 2016.

In the dose-escalation portion of the trial, 44 patients were treated across 10 dose-escalation cohorts. A dose of 10 mg twice daily was recommended for the treatment of an additional 62 patients in the dose-expansion portion of the trial. In the dose-escalation cohorts, there was 1 complete response (CR) lasting more than 3 years in a patient with endometrial cancer, 1 PR in a participant with melanoma, and stable disease (SD) in 18 (41%) patients. In the efficacy-evaluable expansion cohorts, there was 1 PR and 3 PRs with lymphocytosis, all in patients with chronic lymphocytic leukemia. Additonally, there was SD in 64% of 12 patients with castration-resistant prostate cancer, 53% of 18 with head and neck squamous cell carcinoma (HNSCC), 21% of 14 with glioblastoma multiforme, and 22% of 10 with Ewing sarcoma.¹²

AstraZeneca is developing 2 inhibitors of the ATM kinase, AZD0156 and AZD1390. Preclinical studies demonstrated the potential for synergistic activity of AZD0156 in combination with olaparib, and the ongoing phase I AToM study is evaluating this and other combinations, as well as single-agent activity, in patients with advanced solid tumors.

The results of module 1 of this study evaluated the combination of AZD0156 (8 dose cohorts) in combination with olaparib. In recently reported findings for 46 patients, there were 2 confirmed PRs: 1 in a patient with a BRCA2 mutation treated with AZD0156 8 mg once daily for 3 of 7 days plus olaparib 100 mg twice daily, both administered orally, and 1 in a patient with unknown tumor genetics who received AZD0156 30 mg twice daily for 3 of 7 days plus olaparib 100 mg twice daily.¹³

AZD1390 has shown the ability to cross the blood-brain barrier, and profound tumor regression was seen in preclinical models of brain cancer when combined with radiation therapy. A phase I study is curently ongoing.^14,15

Three ATR inhibitors are in clinical development. One early-stage study evaluated the combination of Merck’s M6620 (formerly VX-970) and topotecan in patients with advanced solid tumors. A total of 21 patients were enrolled, and doses up to 1.25 mg/m² of topotecan on days 1 to 5 in combination with M6620 210 mg/m² on days 2 and 5 were well tolerated; among 6 patients treated at the highest dose level, 1 experienced a dose-limiting toxicity of grade 4 thrombocytopenia. The most common grade 3/4 adverse events were anemia, leukopenia, neutropenia, lymphopenia, and thrombocytopenia. There were 2 PRs, and an additional 7 patients experienced SD of 3 months or longer.¹⁶

The results of a separate phase I trial of M6620 in combination with cisplatin in patients with metastatic triple-negative breast cancer were reported at the 2017 San Antonio Breast Cancer Symposium. At the time, 35 patients had been enrolled and treated with cisplatin 75 mg/m² on day 1 in combination with M6620 140 mg/m² on days 2 and 9 of each 21-day cycle.

Median progression-free survival (PFS) was 4.1 months, and preliminary unconfirmed overall response rate (ORR) was 38.9% (all PRs). Grade 3/4 AEs were experienced by 46% of patients and included anemia, neutropenia, vomiting, and nausea.17

A cohort of patients with non—small cell lung cancer (NSCLC), enrolled in the same trial, were the subject of a presentation at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting. Twenty-four patients, who had received up to 2 prior therapies, were evaluable for efficacy. The ORR was 12.5%, all PRs, and 18 additional patients experienced SD, with 4 experiencing PR or SD lasting ≥6 months.¹⁸

Preliminary results from a phase I study of a different ATR inhibitor, AZD6738, were presented at the 2018 American Association for Cancer Research (AACR) Annual Meeting. In patients with advanced solid tumors, this drug was evaluated in 10 dose cohorts from 60 mg once daily to 240 mg twice daily for 5 to 14 days in combination with olaparib 100 to 300 mg twice daily. It was also evaluated in 5 dose cohorts from 80 to 240 mg once daily or twice daily for 1 or 2 weeks in combination with the immune checkpoint inhibitor durvalumab (Imfinzi) 1500 mg on day 1, following a 1- to 2-week monotherapy run-in.

In the olaparib arm, among 39 evaluable patients, there was 1 CR, 5 PRs, and 1 unconfirmed PR in patients with breast, ovarian, prostate, pancreatic, and ampullary cancer. Toxicities included thrombocytopenia, anemia, neutropenia, fatigue, decreased appetite, nausea, and vomiting.

Other DNA Damage Response Targets

The durvalumab arm had 21 evaluable patients, and researchers observed 1 CR, 2 PRs, and 1 unconfirmed PR in patients with NSCLC and HNSCC. Toxicities included fatigue, anemia, nausea, decreased appetite, cough, vomiting, dizziness, pruritus, and constipation.¹⁹Downstream of ATM, ATR, and DNA-PK, other kinases in the DDR signaling network also provide rational targets for anticancer therapy. Among those that have advanced into clinical testing are CHK1/2 inhibitors.

Prexasertib (LY2606368) is a dual inhibitor of CHK1 and CHK2 and continues to be evaluated in a range of phase II clinical trials. Promising results in patients with platinumresistant, relapsed/refractory ovarian cancer were recently published. Among 19 patients who received 105 mg/m² intravenous prexasertib monotherapy every 14 days in 28-day cycles, 32% had a PR and 26% had SD lasting at least 6 months; median PFS was 7.4 months. The most common grade 3/4 AEs were neutropenia, anemia, leukopenia, and thrombocytopenia.²⁰

The results from an expansion cohort of a phase I study of prexasertib involving 101 heavily pretreated patients with squamous cell carcinoma (SCC) of the anus, HNSCC, and squamous NSCLC also were recently published. At 3 months, the clinical benefit rate, defined as the combination of CR, PR, and SD, with singleagent prexasertib therapy was 29% across all SCC types. The median PFS was 2.8 months for patients with SCC of the anus, 1.6 months for those with HNSCC, and 3.0 months for those with squamous NSCLC. The most common treatment- related AE was grade 4 neutropenia.²¹

A selective CHK1 inhibitor, SRA737, is also undergoing clinical investigation. The results of a preclinical study presented at the AACR meeting demonstrated activity of this drug in patients with PARP inhibitor resistance and CCNE1-amplified high-grade serous ovarian cancer.²²

One of the downstream targets of CHK1, in its role in the G2/M checkpoint, is the Wee1 kinase. Adavosertib (AZD1775) is a Wee1 inhibitor that is being evaluated in ongoing phase II clinical trials. Results from a phase I study in patients with refractory solid tumors were presented at the ASCO meeting. Patients received either twice-daily or once-daily dosing in this study, and the results of the latter were the subject of the ASCO presentation; the results from twicedaily dosing were published in 2014.

A total of 28 patients were evaluable for efficacy. The PR rate was 14%, and a further 64% of patients experienced SD; 2 PRs and 6 SDs were observed in patients with BRCA1/2 mutations. The type, prevalence, and severity of AEs were similar with both dosing schedules; anemia, lymphopenia, thrombocytopenia, and fatigue were the most common AEs.^23,24

Posttranslational modifications (PTMs) are a major mechanism for regulating the components of the DDR. In addition to phosphorylation, ubiquitination and a closely related form of PTM, called neddylation, also tightly regulate the activity levels of proteins within the DDR network by targeting them for destruction by the proteasome, the cell’s protein degradation machinery.

Inhibitors of the proteasome itself are already FDA approved for the treatment of multiple myeloma and are being examined for their potential synergy with DDR-targeting agents. Meanwhile, pevonedistat (MLN4924) is a small-molecule inhibitor of Nedd8-activating enzyme. It blocks the neddylation of the Cullin enzymes, which mediate the addition of ubiquitin tags onto target proteins, regulating proteasomal degradation of their target proteins, among which are DNA repair and cell-cycle checkpoint proteins.

To date, pevonedistat has demonstrated the most promising activity in patients with acute myeloid leukemia (AML). In a phase I study, pevonedistat was administered as monotherapy on days 1, 3, and 5 (schedule A; n = 27) or 1, 4, 8, and 11 (schedule B; n = 26) in 21-day cycles. The maximum-tolerated dose (MTD) was 59 mg/m² and 83 mg/m² for schedules A and B, respectively. In patients treated at or below the MTD, the ORR was 17% (including 2 CRs and 2 PRs) for schedule A and 10% (2 PRs) for schedule B.²⁵

In a separate phase IB study, the combination of pevonedistat and the hypomethylating drug azacitidine was evaluated in 64 patients with previously untreated AML. Pevonedistat was administered at a dose of 20 mg/m², elevated to 30 mg/m² in 3 patients, and azacitidine at standard doses. The ORR was 50%, including 20 CRs and 7 PRs, with a median duration of response of 8.3 months. The most common AEs included constipation, anemia, fatigue, nausea, vomiting, and pneumonia.²⁶ These results prompted initiation of a phase III study of this combination in this indication.

Finally, a first-in-class DNA-repair inhibitor, AsiDNA (formerly DT01), also is in clinical development. The drug, which is composed of 32 base pairs of duplex DNA with a cholesterol vector that promotes uptake into cells, functions as an agonist that mimics DNA DSBs, activating DDR pathway components and redirecting them away from sites of tumor DNA damage. That damage goes unrepaired, triggering cancer cell death.

The results of the DRIIM phase I study demonstrated that intratumoral administration in combination with radiotherapy resulted in an ORR of 67% among 21 evaluable patients, including 1 with a CR (5%) and 13 with a PR (62%). Responses were durable, and the drug was well tolerated.²⁷ Onxeo, a biotechnology company based in Paris, France, is testing AsiDNA in combinations in solid tumors with PARP inhibition or chemotherapy and in metastatic melanoma with ratiotherapy.²⁸

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