DNA damage and mutations are at the heart of cancer development and progression. However, cancer cells have adapted to hijack the body's natural DNA repair mechanisms for their own survival and growth. A new class of drugs targeting specific DNA repair pathways is showing promise in clinical trials and may transform cancer treatment in the coming years.

Targeting Damage Response Proteins

One strategy researchers are pursuing is targeting proteins involved in the DNA Repair Drugs damage response (DDR). When DNA is damaged, a complex network of DDR proteins detect the damage and coordinate repair. Some cancer cells become "addicted" to certain DDR proteins to sustain uncontrolled growth. Inhibiting these influential proteins can push cancer cells past their limits.

PARP inhibitors were one of the first DDR drug classes to gain FDA approval. These drugs prevent poly ADP-ribose polymerase (PARP) enzymes from repairing single-strand DNA breaks, ultimately causing double-strand breaks that cancer cells cannot repair. PARP inhibitors such as olaparib and niraparib show benefit in breast and ovarian cancers with BRCA mutations, which impair homologous recombination repair. Beyond BRCA cancers, more research investigates combining PARP inhibitors with chemotherapy or radiotherapy to amplify DNA damage.

Checkpoint Inhibitors Take Aim

Another approach targets molecular checkpoints that monitor DNA integrity and halt the cell cycle if damage is detected. Cancer cells misuse these checkpoints to buy time for error-prone repair or to evade death. Drugs inhibiting checkpoint proteins like ATR, Chk1, and Wee1 force faulty cancer cells down faulty repair pathways.

Combined with DNA-damaging therapies, checkpoint inhibitors drastically enhance efficacy in preclinical models. ATR inhibitors such as AZD6738 gained momentum in early-phase trials, especially against blood cancers. Chk1 blockade also showed synergy with chemotherapy or radiation. In 2021, the Wee1 inhibitor adavosertib entered pivotal trials alongside chemotherapy for solid tumors. With fine-tuned combinations and patient selection, checkpoint drugs may gain similar traction as PARP inhibitors.

Exploiting Repair Pathway Vulnerabilities

Beyond targeting damage signaling, researchers uncover flaws in cancer cells' repair pathways to exploit. Homologous recombination deficiencies due to BRCA mutations exemplify this strategy. Other repair pathways also harbor targets, like base excision repair inhibited by APE1 antagonists or mismatch repair blocked by MSH2/MSH6 inhibitors.

Researchers probe DNA repair drugs pathway regulation as another vulnerability. The tumor suppressor p53 coordinates multiple repair activities and induces apoptosis if damage proves irreparable. Drugs stabilizing mutant p53 reactivate these functions in cancers harboring p53 mutations, which account for over 50% of cases. Likewise, HDAC inhibitors aimed at epigenetic control of repair could improve outcomes when added to standard DNA-damaging therapies.

New Tools Reveal Repair Profiling Potential

Our growing molecular understanding of cancer evolution is enabling repair pathway profiling to guide targeted therapies. DNA repair protein expression, mutational signatures, and CRISPR screening uncover repair reliance in patient tumors and cell lines. Combined with multi-'omics analysis of clinical samples, this profiling yields insights into resistance and sensitivity.

Several biotechs focus on developing companion diagnostics for emerging DNA repair drugs. For example, Myriad Genetics' tumor profiling assay, myChoice CDx, identifies homologous recombination deficiencies and PARP inhibitor sensitivity in solid tumors. Similarly, Foundation Medicine’s FoundationOne CDx analyzes hundreds of cancer-relevant genes to detect DNA repair aberrations.

Moving Forward with Combination Strategies

Given cancer's propensity to develop resistance, combination strategies pair DNA repair drugs inhibitors with standard genotoxic therapies or immune checkpoint drugs. Ongoing trials explore targeting multiple repair pathways simultaneously or sequentially as resistance emerges. Combinatorial DNA damage induction could overwhelm cancer cells' compensatory abilities.

While challenges remain improving target selectivity and combating resistance, DNA repair drugs demonstrate promise as precision oncology agents. Broader applications may emerge from repair pathway characterization across diverse cancer subtypes. Forthcoming data from later-phase trials will guide optimal integration into standard treatment regimens. With researchers nimbly adapting to resistance, DNA repair inhibition may soon transform the way we treat cancer.

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