# New mechanisms of acquired resistance to EGFR-TKIs in Non-small-cell lung cancer

> **NIH NIH R00** · THOMAS JEFFERSON UNIVERSITY · 2022 · $249,000

## Abstract

Abstract
Abnormal oncogenic activation of epidermal growth factor receptor (EGFR) signaling is a key
trigger in inducing various types of cancers including lung cancer, which is recognized as one of
the most important active targets for NSCLC treatment. The application of EGFR-targeted
inhibitors has provided significant benefit for lung cancer patient treatment. However, the
acquisition of resistance to EGFR-targeted inhibitors in cancer cells is the major challenge for
clinicians and oncologists. In addition to known genetic alterations such as EGFR secondary
mutations causing EGFR-TKI resistance, compensatory activation of signaling pathways without
interruption of genome integrity remains to be defined. Our preliminary data showed a persistent
S6K1 activation in resistant non-small lung cancer cells upon EGFR-TKIs treatment, but not in
sensitive cells. Ribosomal protein S6 kinase 1 (S6K1, RPS6KB1), a member of AGC family of
serine/threonine protein kinases and a key effector of the mTORC1 (mammalian target of
rapamycin complex 1), is known to regulates protein synthesis, cell cycle, cell growth and
survival in response to growth factors, and cytokines under both physiological condition and
pathological condition. Deregulation of S6K1 is associated with metastasis and poor prognosis
in lung, colorectal, ovarian, and breast cancer. However the link of S6K1 with drug resistance
remains to be elucidated. We hypothesize that S6K1 activation contributes to the acquired
resistance to EGFR target therapy in NSCLCs. We plan to test this hypothesis through three
aims. Aim 1 is to investigate if S6K1 activation is a new mechanism of acquired resistance to
EGFR target therapy in NSCLC. Aim 2 is to investigate molecular mechanism of EGFR-TKI-
resistance through S6K1 pathway. Aim 3 is to investigate the effect of S6K1 inhibitor
PF4708671 for overcoming EGRF-TKI resistance. The proposal will help to understand new
mechanism in response to EGFR-TKI and to identify S6K1 and its signaling as potential new
druggable target(s). The successful completion of proposed study will provide a potential
therapeutic strategy by overcoming EGFR-TKI resistance for lung cancer treatment in the
future.

## Key facts

- **NIH application ID:** 10328910
- **Project number:** 5R00CA215316-05
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Jun He
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10328910

## Citation

> US National Institutes of Health, RePORTER application 10328910, New mechanisms of acquired resistance to EGFR-TKIs in Non-small-cell lung cancer (5R00CA215316-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10328910. Licensed CC0.

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