# A pan-cancer role for MutL loss in inducing treatment resistance

> **NIH NIH K22** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2020 · $147,169

## Abstract

Project objectives: Dr. Haricharan's long-term career goal is to investigate understudied roles for DNA damage
repair defects in treatment response as an independent cancer researcher in an academic institution with a
well-regarded and collegial biomedical research program. Her objective in the proposed project is to
understand the functional impact of mutations in genes of the MutL complex of mismatch repair on response to
standard-of-care in ER+ breast, colorectal and bladder cancer (Aim 1), establish a novel, poor prognostic role
for MutL genes in bladder and colorectal cancer (Aim 1), and find alternative targeted therapeutics that can
prove efficacious in MutL-defective (MutL-) breast, bladder and colorectal cancer (Aim 2).
Aims and research approach: To achieve these objectives, Aim 1 will investigate the functional impact of
missense mutations in MLH1 that occur in ER+ breast, bladder and colorectal cancer, and test potential
diagnostic assays for MutL loss in vitro and in vivo. Dr. Haricharan has already demonstrated a causal role for
MutL dysregulation in endocrine therapy resistance of ER+ breast cancer. Dr. Haricharan previously identified
vulnerability of MutL- ER+ breast cancer cells to CDK4/6 inhibitors. In Aim 2, she will functionally assess effect
of MutL dysregulation on response to combinatorial CDK4/6 and Bcl inhibitor therapy in clinically informative
patient-derived xenografts (PDXs) and traditional cell line models of ER+ breast, bladder and colorectal cancer.
Relevance to NCI mission: ER+ breast, bladder and colorectal cancer are three of the most common cancers in
the US: ER+ breast cancer is the most common malignancy amongst women, and bladder cancer is the fifth
most common, and colorectal cancer the third most common cancer among men and women alike. Together,
they account for ~100,000 cancer-related deaths in the US every year. This study has the potential to prevent
up to 20% of these deaths. Therefore, this study can significantly impact clinical management of these three
lethal cancers in the short-term, and overturn the research paradigm for mismatch repair dysregulation across
cancer types in the long-term.
Career Development: The proposed work will help Dr. Haricharan's career development by breaking new
ground and exploring the role of MutL loss in bladder and colorectal cancer, since all her previous training has
been in breast cancer. Working extensively with PDXs will also aid Dr. Haricharan's career development by
providing important technical expertise. Additionally, didactic courses in laboratory management and
leadership, and workshops on grantsmanship undertaken during the period of this award will help her acquire
NCI R01 funding and transition smoothly into her independent career.

## Key facts

- **NIH application ID:** 10001982
- **Project number:** 5K22CA229613-03
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Svasti Haricharan
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $147,169
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001982

## Citation

> US National Institutes of Health, RePORTER application 10001982, A pan-cancer role for MutL loss in inducing treatment resistance (5K22CA229613-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001982. Licensed CC0.

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